MicroRNAs(miRNAs)are short noncoding RNAs that regulate the expression of genes by sequence-specific binding to mRNA to either promote or block its translation;they can also act as tumor suppressors(e.g.,let-7b,miR-29...MicroRNAs(miRNAs)are short noncoding RNAs that regulate the expression of genes by sequence-specific binding to mRNA to either promote or block its translation;they can also act as tumor suppressors(e.g.,let-7b,miR-29a,miR-99,mir-100,miR-155,and miR-181)and/or oncogenes(e.g.,miR-29a,miR-125b,miR-143-p3,mir-155,miR-181,miR-183,miR-196b,and miR-223)in childhood acute leukemia(AL).Differentially expressed miRNAs are important factors associated with the initiation and progression of AL.As shown in many studies,they can be used as noninvasive diagnostic and prognostic biomarkers,which are useful in monitoring early stages of AL development or during therapy(e.g.,miR-125b,miR-146b,miR-181c,and miR-4786),accurate classification of different cellular or molecular AL subgroups(e.g.,let-7b,miR-98,miR-100,miR-128b,and miR-223),and identification and development of new therapeutic agents(e.g.,mir-10,miR-125b,miR-203,miR-210,miR-335).Specific miRNA patterns have also been described for commonly used AL therapy drugs(e.g.,miR-125b and miR-223 for doxorubicin,miR-335 and miR-1208 for prednisolone,and miR-203 for imatinib),uncovering miRNAs that are associated with treatment response.In the current review,the role of miRNAs in the development,progression,and therapy monitoring of pediatric ALs will be presented and discussed.展开更多
Using Southern blot, Northern blot and Quick blot methods, we examined the rearrangement and expression of TCR βgene in four early differentiation stage cell lines from human hemopoietic system, namely HL-60, Jurkat,...Using Southern blot, Northern blot and Quick blot methods, we examined the rearrangement and expression of TCR βgene in four early differentiation stage cell lines from human hemopoietic system, namely HL-60, Jurkat, Daudi and Raji cells as well as lymphocytes from 17 acute lymphocytic leukemia （ALL） patients. The results showed. Ⅰ) Rearrangement of TCR βgene was seen in Jurkat cells. A germline pattern was observed in HL-60, Daudi and Raji cells. 2) Eight of 9 patients with T-ALL had cells with rearranged TCR βgene. But two of 3 patients with B-ALL and three of 5 patients with nonT, nonB-ALL also had cells with rearranged TCR βgene. 3) A 1.3 kb full-length transcript and a 1.0 kb truncated transcript were detected in Jurkat cells by probing with <sup>32</sup>P-TCR βcDNA. But some leukemic B cells also expressed an incompleted transcript. 4) TCR βmRNA was detected in six of 8 patients with T-ALL, four of 5 patients with nonT, nonB-ALL and one of 3 patients with B-ALL. But the level of expression was quite differ ent. The dual-rearrangement and the abnormal expression may give us a new clue for researching leukemogenesis.展开更多
The expression of three protooncogenes (c-myc, c-fos, N-ras) in.the primary cells from 53 cases of leukemia as well as peripheral WBC from 8 normal individuals was studied. Semiquantitative analysis of mRNA levels of ...The expression of three protooncogenes (c-myc, c-fos, N-ras) in.the primary cells from 53 cases of leukemia as well as peripheral WBC from 8 normal individuals was studied. Semiquantitative analysis of mRNA levels of the protooncogenes was carried out by Quick-blot. The results showed that (1) c-myc oncogene was slightly expressed and Nras was marginally expressed, whereas the expression of the c-fos was undetectable in the peripheral leucocytes of 8 normal individuals; (2) the c-myc was obviously expressed in almost all leukemic cells irrespective of the cell types, while N-ras and c-fos were variable expressed; (3) the c-fos was expressed in all 4 cases of M4; (4) the c-myc transcript was detected but the N-ras and c-fos were not in 4 chronic leukemic cases; (5) the relationship between protooncogene expression and state of leukemia or after chemotherapy was also analysed.展开更多
In the present study, 98 cases of acute leukemias (AL) were diagnosed and classified based on morphologic, immunologic and cytogenetic (MIC) features to assess their diagnostic value in AL. The results showed that: th...In the present study, 98 cases of acute leukemias (AL) were diagnosed and classified based on morphologic, immunologic and cytogenetic (MIC) features to assess their diagnostic value in AL. The results showed that: the conformity rate of cytomorphologic/cytochemical classification with MIC classification was 90.8%. For ALL, the conformity rate of immunologic classification with MIC classification was 95.6% while it was only 70.8% for AML. Of the 48 AML, 10 expressed lymphoid-lineage-associated antigens and 8 of 43 ALL expressed myeloid-lineage-associated antigens. Seven cases were diagnosed as hybrid acute leukemia according to Catovsky's scoring criterion. The clonal chromosomal aberrations were found in 70 cases, of them 46 cases showed characteristic changes including t(9; 22), t(4; 11), t(11; 14), t(8; 12), t(8; 14), 6q-, 9p- and t(15; 17), t(8; 21), inv(16), etc. These data suggested that MIC classification of acute leukemias could provide more diagnostic and biologic information than traditional FAB classification.展开更多
Metabolic reprogramming is a hallmark of cancer,with acute myeloid leukemia(AML)being no exception.Mitochondrial function,particularly its role in protecting tumor cells against chemotherapy,is of significant interest...Metabolic reprogramming is a hallmark of cancer,with acute myeloid leukemia(AML)being no exception.Mitochondrial function,particularly its role in protecting tumor cells against chemotherapy,is of significant interest in AML chemoresistance.In this study,we identified mitochondrial DNA content(mtDNAc),measured by quantitative PCR,as a simple and precise marker to stratify the metabolic states of AML patients.We show that patients with high mtDNAc are associated with increased mitochondrial metabolism and a higher dependency on oxidative phosphorylation(OXPHOS),often correlating with chemoresistance.Clinically,patients receiving cytarabine and an anthracycline-based regimen(7+3 regimen)experienced inferior relapse-free survival and a higher overall rate of leukemia recurrence.展开更多
To the Editor:Rearrangements involving lysine methyltransferase 2A(KMT2A)represent recurrent genetic abnormalities in acute leukemia(AL),which are commonly associated with poor clinical outcomes.[1]Allogeneic hematopo...To the Editor:Rearrangements involving lysine methyltransferase 2A(KMT2A)represent recurrent genetic abnormalities in acute leukemia(AL),which are commonly associated with poor clinical outcomes.[1]Allogeneic hematopoietic stem cell transplantation(allo-HSCT)can improve long-term survival of KMT2A-rearranged(r)AL,but relapse remains the most important cause of transplant failure.[2]Measurable residual disease(MRD)can predict post-HSCT relapse,and MRD-directed therapies improve clinical outcomes.[3,4]Studies from our center indicate that monitoring the KMT2A level with real-time quantitative polymerase chain reaction(RT-qPCR)can predict relapse and survival post-allo-HSCT.[5,6]Patients positive for KMT2A have a significantly higher cumulative incidence of relapse(93.5%vs.12.5%,P<0.001),a worse overall survival(OS:12.5%vs.77.8%,P<0.001),and a worse leukemia-free survival(LFS,0 vs.72.2%,P<0.001)compared with those continuously negative for KMT2A.展开更多
Acute myeloid leukemia(AML)remains a biologically heterogeneous disease with historically limited targeted therapies and poor outcomes.The development of menin inhibitors represents a promising shift,particularly for ...Acute myeloid leukemia(AML)remains a biologically heterogeneous disease with historically limited targeted therapies and poor outcomes.The development of menin inhibitors represents a promising shift,particularly for patients harboring KMT2A rearrangements(KMT2Ar)and NPM1 mutations(NPM1m).This manuscript reviews the molecular rationale of menin inhibition for aberrant homeobox/myeloid ectopic insertion site 1(HOX/MEIS1)-driven gene expression and leukemogenesis,clinical trial outcomes,and safety data for menin inhibitors,with a focus on recently FDA-approved revumenib and several other agents in development,ziftomenib(KO-539),bleximenib(JNJ-75276617),and icovamenib(BMF-219).We also focused our discussion on future directions to include resistance mechanisms,biomarker identification and monitoring strategies,and combination therapies.Menin inhibition is now being clinically integrated into relapsed/refractory and frontline treatment settings.展开更多
Stem cells are pluripotent cells that can divide and differentiate,forming many different types of cells.Stem cells can be obtained from various sources,with embryonic stem cells being the most advantageous as they po...Stem cells are pluripotent cells that can divide and differentiate,forming many different types of cells.Stem cells can be obtained from various sources,with embryonic stem cells being the most advantageous as they possess a broad dividing potential.When the standard treatment proves ineffective,stem cells are typically utilized as a final option.Infections and childhood malignancies are among the significant causes of mortality in the pediatric population.Stem cell therapy has shown a decrease in morbidity and mortality when used in patients with favorable conditions like young age and lack of comorbidities.This review discusses how stem cells are prepared and used in treating pediatric diseases like X-linked agammaglobulinemia,diabetes mellitus,aplastic anemia,infections,and leukemia.Technological advancement has played a significant role in producing more specific stem cells using genetic modification methods like clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9,which produce stem cells that target a particular cell type,e.g.,myocytes and hematopoietic cells,further increasing the effectiveness of the therapy.We address the obstacles faced when conducting research related to stem cells,including ethical and legal issues,which hinder the use of this therapy in some fields.We also indicate recommendations for increasing the efficacy of stem cell therapy in the pediatric population.展开更多
This study systematically analyzed the primary causes of malnutrition in children with leukemia during chemotherapy,clarified the status of malnutrition and specific nutritional intervention measures,and comprehensive...This study systematically analyzed the primary causes of malnutrition in children with leukemia during chemotherapy,clarified the status of malnutrition and specific nutritional intervention measures,and comprehensively evaluated the research progress.The research indicates a shift from basic supportive care toward precision intervention strategies.Immunonutrition approaches,such as omega-3 fatty acid supplementation and probiotics for gut microbiota modulation,significantly mitigate chemotherapy-related side effects and enhance nutritional status.These targeted novel regimens demonstrate clear clinical advantages.The success of nutritional management depends on a multidisciplinary collaboration mechanism.The organic integration of innovative nutritional protocols with standard treatments from hematology,pediatrics,and nutrition departments significantly optimizes treatment outcomes and long-term quality of life for children with leukemia.This interdisciplinary synergy is reshaping contemporary medical models.展开更多
Objectives:Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia and Philadelphia-like B-cell acute lymphoblastic leukemia(Ph+/Ph-like ALL)constitute the majority of relapsed/refractory B-ALL(R/R B-ALL)...Objectives:Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia and Philadelphia-like B-cell acute lymphoblastic leukemia(Ph+/Ph-like ALL)constitute the majority of relapsed/refractory B-ALL(R/R B-ALL)cases,highlighting an urgent need to discover new therapeutic targets.This study aims to elucidate the mechanisms underlying poor prognosis in Ph+/Ph-like ALL through transcriptome sequencing and functional cytological assays,with the goal of informing new clinical treatment strategies.Results:Transcriptomic analysis of Ph+/Ph-like ALL patients revealed that low expression of P2X Purinoceptor 1(P2RX1)was associated with unfavorable outcomes.Specifically,patients with poor prognosis and low P2RX1 expression exhibited downregulation of genes involved in energy and calcium metabolism pathways,along with upregulation of genes governing key cellular processes such as cell proliferation(e.g.,MYC),cell cycle progression(e.g.,CCND2),and apoptosis inhibition(e.g.,DASP6).Cellular experiments demonstrated that SUP-B15 cells overexpressing P2RX1 displayed elevated intracellular levels of ATP,calcium,and glucose,together with enhanced glycolytic capacity,compared to empty vector controls.Treatment of SUP-B15 cells with dexamethasone(Dex),Imatinib,or their combination significantly suppressed proliferation and promoted apoptosis,which was accompanied by increases in intracellular ATP,calcium,and glucose.Moreover,exogenous ATP administration(a P2RX1 agonist)enhanced apoptosis and inhibited proliferation in control cells.Conversely,treatment with NF449(a P2RX1 inhibitor)increased proliferation in both P2RX1-overexpressing and control SUP-B15 cells.Conclusion:Our findings indicate that P2RX1 may exert this function through modulating energy metabolism and calcium homeostasis,resulting in elevated intracellular calcium levels.Sustained elevation of calcium promotes apoptosis,whereas exogenous ATP activates P2RX1,enhances calcium influx,and attenuates the suppression of apoptosis associated with P2RX1 underexpression,ultimately correlating with improved treatment response.展开更多
Background:Childhood leukemia,a malignant proliferative disorder of the hematopoietic system and the most common childhood cancer,poses a significant threat to the lives and health of affected children.For parents,a l...Background:Childhood leukemia,a malignant proliferative disorder of the hematopoietic system and the most common childhood cancer,poses a significant threat to the lives and health of affected children.For parents,a leukemia diagnosis in their child is a profoundly traumatic event.As primary caregivers,they endure immense psychological distress and caregiving stress throughout the prolonged and demanding treatment process,which can adversely affect their own well-being and caregiving capacity.However,the psychological mechanisms,such as the role of mindfulness,linking caregiver stress to parental coping strategies remain underexplored,and evidence-based interventions to support these parents are needed.Methods:In Study 1,we administered a cross-sectional survey to 242 parents of children with leukemia who were hospitalized at the Affiliated Hospital of Qingdao University between January and August 2024.Participants completed measures assessing caregiver burden,mindful attention awareness,and parental coping style.In Study 2,we further evaluated the effects of a Mindfulness-Based Stress Reduction(MBSR)intervention.Results:The results of Study 1 revealed:(1)The caregiving stress significantly and negatively predicted coping style(β=−1.18,95%CI[−2.18,−0.18],p<0.01).(2)Caregiving stress also significantly and negatively predicted mindfulness(β=−1.90,95%CI[−2.43,−1.38],p<0.01).(3)Conversely,mindfulness significantly and positively predicted coping style(β=0.85,95%CI[0.62,1.07],p<0.01).These findings suggest that mindfulness mediates the relationship between caregiver burden and coping style.In Study 2,the experimental group showed a significant decrease in caregiver stress post-intervention(t=2.24,p<0.05),a significant increase in mindfulness(t=−4.61,p<0.001),and a significant improvement in coping style(t=−2.36,p<0.01).No significant changes were observed in the control group.Conclusion:MBSR can effectively enhance mindfulness and promote adaptive coping strategies,while reducing caregiver burden among parents of children with leukemia.展开更多
Objectives Chronic lymphocytic leukemia(CLL)is characterized by progressive immune dysregulation.Invariant natural killer T(iNKT)cells support immune surveillance,but the clinical relevance of their regulatory subsets...Objectives Chronic lymphocytic leukemia(CLL)is characterized by progressive immune dysregulation.Invariant natural killer T(iNKT)cells support immune surveillance,but the clinical relevance of their regulatory subsets remains unclear.FoxP3+regulatory iNKT cells(iNKTreg)and E4BP4+IL-10+(iNKT10)cells may reflect immunoregulatory changes associated with disease progression.The study aimed to quantify circulating iNKTreg and iNKT10 subsets and monocytic myeloid-derived suppressor cells(M-MDSCs)in treatment-naïve CLL patients and evaluate their associations with disease characteristics and time to first treatment(TTFT).Methods Peripheral blood samples from 60 untreated CLL patients and 20 healthy donors were analyzed by flow cytometry to determine iNKTreg and iNKT10 percentages,as well as indoleamine 2,3-dioxygenase(IDO)-expressing M-MDSCs.Receiver operating characteristic(ROC)curves and Cox proportional hazards models were used to assess prognostic significance.Results iNKTreg and iNKT10 percentages were significantly increased in CLL compared with healthy donors(p=0.002).Elevated iNKTreg frequencies were associated with zeta-chain-associated protein of 70 kD(ZAP-70)positivity(p=0.017),CD38 positivity(p=0.048),and treatment requirement during follow-up(p=0.016).Based on an ROC-derived cut-off of 9.6%(AUC=0.753),patients with iNKTreg≥9.6%had shorter TTFT(hazard ratio[HR]=2.71;95%confidence interval[CI],1.13–6.49;p=0.025),although the association was not retained in multivariate analysis(HR=1.27;95%CI,0.44–3.64;p=0.626).iNKTreg and iNKT10 percentages correlated positively with IDO+M-MDSCs(p=0.035 and p=0.044),but not with arginase-1(ARG1)or inducible nitric oxide synthase(NOS2).Conclusion Elevated iNKTreg levels reflect a more aggressive disease phenotype and associate with shorter TTFT in univariate analysis,supporting their exploration as complementary immunological biomarkers in CLL.Functional studies and validation in larger cohorts are needed to determine their prognostic and biological significance.展开更多
Background:Breakpoint Cluster Region-Abelson(BCR::ABL1)fusion protein is essential in the pathogenesis of chronic myeloid leukemia(CML);however,the chronic-to-blast phase transformation remains elusive.We identified n...Background:Breakpoint Cluster Region-Abelson(BCR::ABL1)fusion protein is essential in the pathogenesis of chronic myeloid leukemia(CML);however,the chronic-to-blast phase transformation remains elusive.We identified novel kinesin light chain 2(KLC2)mutations in CML-myeloid blast phase patients.We aimed to examine the functional role of KLC2 mutations in leukemogenesis.Methods:To evaluate the biological role of KLC2 mutants(MT)in CML cells,we expressed KLC2-MT in different human CML cell lines harboring BCR::ABL1 and performed immunoblot,immunofluorescence,cell proliferation,differentiation,and apoptosis;Tyrosine kinase inhibitor(TKI)-drug activities;and clonogenic assays for in vitro functional analyses.We co-expressed KLC2-MT and BCR::ABL1 in mouse bone marrow cells(BMCs)to evaluate their clonogenic and self-renewal abilities ex vivo.Furthermore,we examined tumorigenic activity and drug efficacy in the K562 xenograft model.Results:KLC2-MT overexpression in BCR::ABL1-positive K562 and KU812 CML cells promoted cell proliferation and clonogenic potential,decreased imatinib sensitivity,and reduced apoptosis.Serial colony replating assays revealed that KLC2-MT and BCR::ABL1 co-expression enhanced the self-renewal ability of mouse BMCs with immature morphology.In the K562 xenograft model,KLC2-MT enhanced tumorigenic potential and diminished imatinib efficacy.Further studies reported that KLC2-MT augmented signal transducer and activator of transcription 3(STAT3)activation and nuclear accumulation in imatinib-treated CML cells.KLC2-WT and KLC2-MT interacted with mothers against decapentaplegic homolog 2(SMAD2);however,the latter impaired transforming growth factor-beta(TGF-β)–mediated SMAD2/3 activation while enhancing STAT3 phosphorylation.Conclusions:This study demonstrates the biological and functional importance of KLC2 mutation in CML cells,potentially enabling the development of better treatment strategies for CML patients carrying KLC2 mutations and providing enhanced understanding of the disease progression.展开更多
Background Myelodysplastic syndromes (MDSs), also called preleukemias, are a group of myeloid hematopoietic malignant disorders. We studied the transformation of MDS into acute myeloid leukemia (AML).Methods Leukemi...Background Myelodysplastic syndromes (MDSs), also called preleukemias, are a group of myeloid hematopoietic malignant disorders. We studied the transformation of MDS into acute myeloid leukemia (AML).Methods Leukemic transformation in 151 patients with MDS was dynamically followed up. The clinical manifestation, peripheral blood and bone marrow condition, karyotypes, immunophenotypes, response to treatment, and prognosis of AML evolution from MDS (MDS-AML) were also observed.Results During the course of this study, over the past eight years and seven months, 21 (13.91%) of 151 MDS patients progressed to overt leukemia, with a median interval of 5 (1-23) months. There were no significant differences between rates of leukemic transformation in comparison with the refractory anemia (RA), RA with excess of blasts (RAEB), and RAEB in transformation (RAEB-t) patient groups. Transformation occurred either gradually or rapidly. There were five parameters positively correlated to leukemic transformation: under 40 years of age, pancytopenia of 3 lineages, more than 15% blasts in the bone marrow, at least two abnormal karyotypes, and treatment with combined chemotherapy. All of the 21 patients with leukemia suffered from MDS-AML, and most of them were M 2, M 4, or M 5. Two (9.52%) MDS-AML patients developed extramedullary infiltration. Leukopenia was found in 47.62% of these patients. Two thirds of these patients, whose bone marrows were generally hypercellular, suffered from neutropenia. After developing AML, 8 (47.06%) patients developed abnormal karyotypes. High expression of immature myeloid antigens, including CD 33 [(49.83±24.50)%], CD 13 [(36.38±33.84)%], monocytic antigen CD 14 [(38.50±24.60)%], and stem cell marker CD 34 [(34.67±30.59)%], were found on bone marrow mononuclear cells from MDS-AML patients after leukemic transformation. In some cases, lymphoid antigens, such as CD 5, CD 7, CD 9, and CD 19, coexisted with myeloid antigens. A low complete remission rate (31.25%) and a short survival time, with median survival of 6 (1-28) months, were found in patients with MDS-AML treated by induction chemotherapy.Conclusions MDS has a high risk of developing into AML, either gradually or rapidly. Patients with MDS-AML have specific biological characteristics and a worse prognosis.展开更多
Background Both in vitro and in vivo data have demonstrated the TGFBI gene functions as a putative tumor suppressor and is frequently downregulated in human tumors of different histological types.The hypermethylation ...Background Both in vitro and in vivo data have demonstrated the TGFBI gene functions as a putative tumor suppressor and is frequently downregulated in human tumors of different histological types.The hypermethylation of the TGFBI promoter,as one of the main regulatory mechanisms,is associated with TGFBI silencing.In this study,we used a methylation-specific PCR （MSP） method to evaluate the methylation status of the TGFBI promoter in human leukemias.Methods Real-time RT-PCR and methylation-specific PCR approaches were performed to define the TGFBI expression and promoter methylation in human leukemia call lines and clinical samples.Genomic DNA was isolated from peripheral blood mononuclear cells from leukemia patients,bisulfite-converted,and analyzed by the MSP method.Results Hypermethylation of the TGFBI promoter occurred in leukemia cell lines and demethylation treatment reexpressed TGFBI at a substantially increased level in most of leukemia cell lines tested.Furthermore,a much higher level of CpG island methylation and a significantly lower TGFBI expression were also identified in clinical leukemia samples.Conclusion The results suggest an important role of promoter methylation in regulating TGFBI expression in leukemia,which provides a useful diagnostic marker for clinical management of human leukemias.展开更多
Aim:The main goal of this study was to elucidate at the transcript level the tyrosine kinase expression profiles of primary leukemia cells from mixed lineage leukemia 1 gene rearranged(KMT2A/MLL-R+)acute myeloid leuke...Aim:The main goal of this study was to elucidate at the transcript level the tyrosine kinase expression profiles of primary leukemia cells from mixed lineage leukemia 1 gene rearranged(KMT2A/MLL-R+)acute myeloid leukemia(AML)and acute lymphoblastic leukemia(ALL)patients.Methods:We evaluated protein tyrosine kinase(PTK)gene expression profiles of primary leukemic cells in KMT2A/MLL-R+AML and ALL patients using publicly available archived datasets.Results:Our studies provided unprecedented evidence that the genetic signatures of KMT2A/MLL-R+AML and ALL cells are characterized by transcript-level overexpression of specific PTK.In infants,children and adults with KMT2A/MLL-R+ALL,as well as pediatric patients with KMT2A/MLL-R+AML,the gene expression levels for FLT3,BTK,SYK,JAK2/JAK3,as well as several SRC family PTK were differentially amplified.In adults with KMT2A/MLLR+AML,the gene expression levels for SYK,JAK family kinase TYK2,and the SRC family kinases FGR and HCK were differentially amplified.Conclusion:These results provide new insights regarding the clinical potential of small molecule inhibitors of these PTK,many of which are already FDA/EMA-approved for other indications,as components of innovative multimodality treatment platforms against KMT2A/MLL-R+acute leukemias.展开更多
Aim:CD22ΔE12 as an oncogenic driver lesion in aggressive and drug-resistant B-precursor acute lymphoblastic leukemia(BPL)cells.The purpose of the present study was to identify the CD22ΔE12-specific signature transcr...Aim:CD22ΔE12 as an oncogenic driver lesion in aggressive and drug-resistant B-precursor acute lymphoblastic leukemia(BPL)cells.The purpose of the present study was to identify the CD22ΔE12-specific signature transcriptome in human BPL cells and evaluate the clinical potential of a nanoscale formulation of CD22ΔE12-siRNA as an RNAi therapeutic against drug-resistant BPL.CD22ΔE12-siRNA nanoparticles significantly improved the event-free survival(EFS)outcome of NOD/SCID(NS)mice challenged with human BPL xenograft cells.Methods:Gene expression and translational bioinformatics methods were applied to examine the expression of the CD22ΔE12-specific signature transcriptome in human BPL cells in subsets of BPL patients.Survival analysis for mice challenged with BPL cells and treated with CD22ΔE12 siRNA was performed using standard methods.Results:Leukemia cells from CD22ΔE12-Tg mice exhibit gene and protein expression profiles consistent with constitutive activation of multiple signaling networks,mimicking the profiles of relapsed BPL patients as well as newly diagnosed high-risk patients with BCR-ABL+/Philadelphia chromosome(Ph)+BPL as well as Ph-like BPL.A nanoscale formulation of CD22ΔE12-siRNA abrogated the in vivo clonogenicity of the leukemia-initiating leukemic cell fraction in xenograft specimens derived from patients with relapsed BPL and significantly improved the EFS outcome of NS mice challenged with drug-resistant human BPL xenograft cells.Conclusion:The CD22-RNAi technology is applicable to all BPL patients both high risk and standard risk.That is because CD22ΔE12 is a characteristic feature of drug-resistant leukemic clones that escape chemotherapy and cause relapse in both high risk and low risk subgroups of patients.The technology therefore has the potential(1)for prevention of relapses by selectively killing the clones that are most likely to escape chemotherapy and cause relapse as well(2)for treatment of relapses in BPL.This research project may also lead to innovative salvage regimens against other forms of CD22ΔE12-positive relapsed B-lineage leukemias and lymphomas.展开更多
Objective:Adverse-risk acute myeloid leukemia(AML)patients should receive allogeneic hematopoietic stem cell transplantation(allo-HSCT)at first complete remission(CR1).However,the influence of prior therapies[i.e.,ven...Objective:Adverse-risk acute myeloid leukemia(AML)patients should receive allogeneic hematopoietic stem cell transplantation(allo-HSCT)at first complete remission(CR1).However,the influence of prior therapies[i.e.,venetoclax plus azacitidine(VEN-AZA)or intensive chemotherapy(IC)]on post-transplant outcomes remains inconclusive.This multicenter,retrospective study compared the post-transplant outcomes between patients receiving VEN-AZA and those receiving IC before allo-HSCT.Methods:This study was based on the transplant database of TROPHY group.Consecutive adverse-risk AML patients receiving allo-HSCT from January 2021 to June 2023 were screened in five Chinese transplant centers.Patients were categorized into VEN-AZA group if they received venetoclax combined with azacitidine as first-line therapy followed by allo-HSCT.Patients who received first-line therapy consisting of a mainstay treatment of cytarabine and anthracycline followed by allo-HSCT were categorized into IC group.Results:In the total cohort,the 3-year probabilities of overall survival,leukemia-free survival,and event-free survival were better in the IC group than VEN-AZA group,particularly for patients with ASXL1 mutations or SF3B1 mutations.However,the survival of the VEN-AZA group was not superior to that of IC group in patients aged≥55 years or those with the hematopoietic cell transplantation-comorbidity index scores≥1 before allo-HSCT.After propensity score matching(median age:VEN-AZA group:57 years;IC group:55 years),only the probability of overall survival for the IC group was better than that of VEN-AZA group(93.6%vs.78.0%,P=0.034)at the 1-year follow-up;however,all of the other clinical outcomes were comparable between the VEN-AZA and IC groups.The TP53 mutation was independently associated with post-transplant relapse and survival.Conclusions:Our results suggest that IC remains the cornerstone of therapy,whereas VEN-AZA may also be used in younger patients and medically fit patients with adverse-risk AML who are receiving allo-HSCT in CR1.展开更多
Patients with leukemia often suffer from the combined effects of cancer-related fatigue(CRF)and subthreshold depression,which mutually exacerbate each other in a vicious cycle.In this editorial,we comment on the artic...Patients with leukemia often suffer from the combined effects of cancer-related fatigue(CRF)and subthreshold depression,which mutually exacerbate each other in a vicious cycle.In this editorial,we comment on the article by Liu et al,published in the World Journal of Psychiatry.We further elucidate the profound impact of subthreshold depressive symptoms on the experience of CRF and complications in patients with leukemia.This editorial highlights the importance of early identification and treatment of subclinical depression,and advocates for a multidisciplinary and integrated treatment approach that includes social support,psychological interventions,and individualized treatment plans.Future research needs to explore the biological mechanisms underlying the interaction between the two to develop more effective prevention and treatment strategies.展开更多
BACKGROUND Acute myeloid leukemia(AML)is a complicated disease with uncontrolled hematopoietic precursor proliferation induced by various genetic alterations.Runt-related transcription factor-1(RUNX1)is commonly disru...BACKGROUND Acute myeloid leukemia(AML)is a complicated disease with uncontrolled hematopoietic precursor proliferation induced by various genetic alterations.Runt-related transcription factor-1(RUNX1)is commonly disrupted by chromosomal translocations in hematological malignancies.AIM To characterize RUNX1 gene rearrangements and copy number variations in newly diagnosed adult AML patients,with an emphasis on the impact of clinical and laboratory features on the outcome.METHODS Fluorescence in situ hybridization was used to test RUNX1 gene alterations in 77 newly diagnosed adult AML cases.NPM1,FLT3/ITD,FLT3/TKD,and KIT mutations were tested by PCR.Prognostic clinical and laboratory findings were studied in relation to RUNX1 alterations.RESULTS RUNX1 abnormalities were detected by fluorescence in situ hybridization in 41.6%of patients:20.8%had translocations,22.1%had amplification,and 5.2%had deletion.Translocations prevailed in AML-M2(P=0.019)with a positive expression of myeloperoxidase(P=0.031),whereas deletions dominated in M4 and M5 subtypes(P=0.008)with a positive association with CD64 expression(P=0.05).The modal chromosomal number was higher in cases having amplifications(P=0.007)and lower in those with deletions(P=0.008).RUNX1 abnormalities were associated with complex karyotypes(P<0.001)and were mutually exclusive of NPM1 mutations.After 44 months of follow-up,RUNX1 abnormalities affected neither patients’response to treatment nor overall survival.CONCLUSION RUNX1 abnormalities were mutually exclusive of NPM1 mutations.RUNX1 abnormalities affected neither patients’response to treatment nor overall survival.展开更多
文摘MicroRNAs(miRNAs)are short noncoding RNAs that regulate the expression of genes by sequence-specific binding to mRNA to either promote or block its translation;they can also act as tumor suppressors(e.g.,let-7b,miR-29a,miR-99,mir-100,miR-155,and miR-181)and/or oncogenes(e.g.,miR-29a,miR-125b,miR-143-p3,mir-155,miR-181,miR-183,miR-196b,and miR-223)in childhood acute leukemia(AL).Differentially expressed miRNAs are important factors associated with the initiation and progression of AL.As shown in many studies,they can be used as noninvasive diagnostic and prognostic biomarkers,which are useful in monitoring early stages of AL development or during therapy(e.g.,miR-125b,miR-146b,miR-181c,and miR-4786),accurate classification of different cellular or molecular AL subgroups(e.g.,let-7b,miR-98,miR-100,miR-128b,and miR-223),and identification and development of new therapeutic agents(e.g.,mir-10,miR-125b,miR-203,miR-210,miR-335).Specific miRNA patterns have also been described for commonly used AL therapy drugs(e.g.,miR-125b and miR-223 for doxorubicin,miR-335 and miR-1208 for prednisolone,and miR-203 for imatinib),uncovering miRNAs that are associated with treatment response.In the current review,the role of miRNAs in the development,progression,and therapy monitoring of pediatric ALs will be presented and discussed.
文摘Using Southern blot, Northern blot and Quick blot methods, we examined the rearrangement and expression of TCR βgene in four early differentiation stage cell lines from human hemopoietic system, namely HL-60, Jurkat, Daudi and Raji cells as well as lymphocytes from 17 acute lymphocytic leukemia （ALL） patients. The results showed. Ⅰ) Rearrangement of TCR βgene was seen in Jurkat cells. A germline pattern was observed in HL-60, Daudi and Raji cells. 2) Eight of 9 patients with T-ALL had cells with rearranged TCR βgene. But two of 3 patients with B-ALL and three of 5 patients with nonT, nonB-ALL also had cells with rearranged TCR βgene. 3) A 1.3 kb full-length transcript and a 1.0 kb truncated transcript were detected in Jurkat cells by probing with <sup>32</sup>P-TCR βcDNA. But some leukemic B cells also expressed an incompleted transcript. 4) TCR βmRNA was detected in six of 8 patients with T-ALL, four of 5 patients with nonT, nonB-ALL and one of 3 patients with B-ALL. But the level of expression was quite differ ent. The dual-rearrangement and the abnormal expression may give us a new clue for researching leukemogenesis.
文摘The expression of three protooncogenes (c-myc, c-fos, N-ras) in.the primary cells from 53 cases of leukemia as well as peripheral WBC from 8 normal individuals was studied. Semiquantitative analysis of mRNA levels of the protooncogenes was carried out by Quick-blot. The results showed that (1) c-myc oncogene was slightly expressed and Nras was marginally expressed, whereas the expression of the c-fos was undetectable in the peripheral leucocytes of 8 normal individuals; (2) the c-myc was obviously expressed in almost all leukemic cells irrespective of the cell types, while N-ras and c-fos were variable expressed; (3) the c-fos was expressed in all 4 cases of M4; (4) the c-myc transcript was detected but the N-ras and c-fos were not in 4 chronic leukemic cases; (5) the relationship between protooncogene expression and state of leukemia or after chemotherapy was also analysed.
文摘In the present study, 98 cases of acute leukemias (AL) were diagnosed and classified based on morphologic, immunologic and cytogenetic (MIC) features to assess their diagnostic value in AL. The results showed that: the conformity rate of cytomorphologic/cytochemical classification with MIC classification was 90.8%. For ALL, the conformity rate of immunologic classification with MIC classification was 95.6% while it was only 70.8% for AML. Of the 48 AML, 10 expressed lymphoid-lineage-associated antigens and 8 of 43 ALL expressed myeloid-lineage-associated antigens. Seven cases were diagnosed as hybrid acute leukemia according to Catovsky's scoring criterion. The clonal chromosomal aberrations were found in 70 cases, of them 46 cases showed characteristic changes including t(9; 22), t(4; 11), t(11; 14), t(8; 12), t(8; 14), 6q-, 9p- and t(15; 17), t(8; 21), inv(16), etc. These data suggested that MIC classification of acute leukemias could provide more diagnostic and biologic information than traditional FAB classification.
基金supported by Fundação de AmparoàPesquisa do Estado de São Paulo(FAPESP,Grant#2013/08135-2,CNPq:465539/2014-9)D.A.P-M.Received a fellowship from FAPESP(Grant#2017/23117-1)+2 种基金I.W.received a fellowship from FAPESP(Grant#2015/09228-0)L.Q.and P.C.were funded by UKRI/MRC grant#MR/R007608/1.A.R.L-A.Received a research grant and fellowship from Conselho Nacional de Desenvolvimento Científico e Tecnológico(CNPq,Grant#303479/2018-3,#405918/2022-4)I.W and D.A.P-M were sponsored by the Abel Tasman Talent Program(ATTP)of the Graduate School of Medical Sciences of the University of Groningen/University Medical Center Groningen(UG/UMCG),The Netherlands.
文摘Metabolic reprogramming is a hallmark of cancer,with acute myeloid leukemia(AML)being no exception.Mitochondrial function,particularly its role in protecting tumor cells against chemotherapy,is of significant interest in AML chemoresistance.In this study,we identified mitochondrial DNA content(mtDNAc),measured by quantitative PCR,as a simple and precise marker to stratify the metabolic states of AML patients.We show that patients with high mtDNAc are associated with increased mitochondrial metabolism and a higher dependency on oxidative phosphorylation(OXPHOS),often correlating with chemoresistance.Clinically,patients receiving cytarabine and an anthracycline-based regimen(7+3 regimen)experienced inferior relapse-free survival and a higher overall rate of leukemia recurrence.
基金supported by grants from the National Key Research and Development Program of China(No.2017YFA0104500)CAMS Innovation Fund for Medical Sciences(CIFMS)(No.2019-I2M-5-034)+3 种基金the Capital’s Funds for Health Improvement and Research(No.2018-4-4089)the Foundation for Innovative Research Groups of the National Natural Science Foundation of China(No.81621001)the Program of the National Natural Science Foundation of China(Nos.81900173 and 82170208)the Key Program of the National Natural Science Foundation of China(No.81930004).
文摘To the Editor:Rearrangements involving lysine methyltransferase 2A(KMT2A)represent recurrent genetic abnormalities in acute leukemia(AL),which are commonly associated with poor clinical outcomes.[1]Allogeneic hematopoietic stem cell transplantation(allo-HSCT)can improve long-term survival of KMT2A-rearranged(r)AL,but relapse remains the most important cause of transplant failure.[2]Measurable residual disease(MRD)can predict post-HSCT relapse,and MRD-directed therapies improve clinical outcomes.[3,4]Studies from our center indicate that monitoring the KMT2A level with real-time quantitative polymerase chain reaction(RT-qPCR)can predict relapse and survival post-allo-HSCT.[5,6]Patients positive for KMT2A have a significantly higher cumulative incidence of relapse(93.5%vs.12.5%,P<0.001),a worse overall survival(OS:12.5%vs.77.8%,P<0.001),and a worse leukemia-free survival(LFS,0 vs.72.2%,P<0.001)compared with those continuously negative for KMT2A.
文摘Acute myeloid leukemia(AML)remains a biologically heterogeneous disease with historically limited targeted therapies and poor outcomes.The development of menin inhibitors represents a promising shift,particularly for patients harboring KMT2A rearrangements(KMT2Ar)and NPM1 mutations(NPM1m).This manuscript reviews the molecular rationale of menin inhibition for aberrant homeobox/myeloid ectopic insertion site 1(HOX/MEIS1)-driven gene expression and leukemogenesis,clinical trial outcomes,and safety data for menin inhibitors,with a focus on recently FDA-approved revumenib and several other agents in development,ziftomenib(KO-539),bleximenib(JNJ-75276617),and icovamenib(BMF-219).We also focused our discussion on future directions to include resistance mechanisms,biomarker identification and monitoring strategies,and combination therapies.Menin inhibition is now being clinically integrated into relapsed/refractory and frontline treatment settings.
文摘Stem cells are pluripotent cells that can divide and differentiate,forming many different types of cells.Stem cells can be obtained from various sources,with embryonic stem cells being the most advantageous as they possess a broad dividing potential.When the standard treatment proves ineffective,stem cells are typically utilized as a final option.Infections and childhood malignancies are among the significant causes of mortality in the pediatric population.Stem cell therapy has shown a decrease in morbidity and mortality when used in patients with favorable conditions like young age and lack of comorbidities.This review discusses how stem cells are prepared and used in treating pediatric diseases like X-linked agammaglobulinemia,diabetes mellitus,aplastic anemia,infections,and leukemia.Technological advancement has played a significant role in producing more specific stem cells using genetic modification methods like clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9,which produce stem cells that target a particular cell type,e.g.,myocytes and hematopoietic cells,further increasing the effectiveness of the therapy.We address the obstacles faced when conducting research related to stem cells,including ethical and legal issues,which hinder the use of this therapy in some fields.We also indicate recommendations for increasing the efficacy of stem cell therapy in the pediatric population.
文摘This study systematically analyzed the primary causes of malnutrition in children with leukemia during chemotherapy,clarified the status of malnutrition and specific nutritional intervention measures,and comprehensively evaluated the research progress.The research indicates a shift from basic supportive care toward precision intervention strategies.Immunonutrition approaches,such as omega-3 fatty acid supplementation and probiotics for gut microbiota modulation,significantly mitigate chemotherapy-related side effects and enhance nutritional status.These targeted novel regimens demonstrate clear clinical advantages.The success of nutritional management depends on a multidisciplinary collaboration mechanism.The organic integration of innovative nutritional protocols with standard treatments from hematology,pediatrics,and nutrition departments significantly optimizes treatment outcomes and long-term quality of life for children with leukemia.This interdisciplinary synergy is reshaping contemporary medical models.
基金supported by Guangdong Province Basic and Applied Basic Research Fund Project(2023A1515220104)Open Fund of Key Laboratory of Hepatoaplenic Surgery,Ministry of Education(Award Number:GPKF202407).
文摘Objectives:Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia and Philadelphia-like B-cell acute lymphoblastic leukemia(Ph+/Ph-like ALL)constitute the majority of relapsed/refractory B-ALL(R/R B-ALL)cases,highlighting an urgent need to discover new therapeutic targets.This study aims to elucidate the mechanisms underlying poor prognosis in Ph+/Ph-like ALL through transcriptome sequencing and functional cytological assays,with the goal of informing new clinical treatment strategies.Results:Transcriptomic analysis of Ph+/Ph-like ALL patients revealed that low expression of P2X Purinoceptor 1(P2RX1)was associated with unfavorable outcomes.Specifically,patients with poor prognosis and low P2RX1 expression exhibited downregulation of genes involved in energy and calcium metabolism pathways,along with upregulation of genes governing key cellular processes such as cell proliferation(e.g.,MYC),cell cycle progression(e.g.,CCND2),and apoptosis inhibition(e.g.,DASP6).Cellular experiments demonstrated that SUP-B15 cells overexpressing P2RX1 displayed elevated intracellular levels of ATP,calcium,and glucose,together with enhanced glycolytic capacity,compared to empty vector controls.Treatment of SUP-B15 cells with dexamethasone(Dex),Imatinib,or their combination significantly suppressed proliferation and promoted apoptosis,which was accompanied by increases in intracellular ATP,calcium,and glucose.Moreover,exogenous ATP administration(a P2RX1 agonist)enhanced apoptosis and inhibited proliferation in control cells.Conversely,treatment with NF449(a P2RX1 inhibitor)increased proliferation in both P2RX1-overexpressing and control SUP-B15 cells.Conclusion:Our findings indicate that P2RX1 may exert this function through modulating energy metabolism and calcium homeostasis,resulting in elevated intracellular calcium levels.Sustained elevation of calcium promotes apoptosis,whereas exogenous ATP activates P2RX1,enhances calcium influx,and attenuates the suppression of apoptosis associated with P2RX1 underexpression,ultimately correlating with improved treatment response.
基金approved by the Ethics Review Committee of Northwest Normal University(Approval No.:[2023028]).All participants signed the informed consent in this study.
文摘Background:Childhood leukemia,a malignant proliferative disorder of the hematopoietic system and the most common childhood cancer,poses a significant threat to the lives and health of affected children.For parents,a leukemia diagnosis in their child is a profoundly traumatic event.As primary caregivers,they endure immense psychological distress and caregiving stress throughout the prolonged and demanding treatment process,which can adversely affect their own well-being and caregiving capacity.However,the psychological mechanisms,such as the role of mindfulness,linking caregiver stress to parental coping strategies remain underexplored,and evidence-based interventions to support these parents are needed.Methods:In Study 1,we administered a cross-sectional survey to 242 parents of children with leukemia who were hospitalized at the Affiliated Hospital of Qingdao University between January and August 2024.Participants completed measures assessing caregiver burden,mindful attention awareness,and parental coping style.In Study 2,we further evaluated the effects of a Mindfulness-Based Stress Reduction(MBSR)intervention.Results:The results of Study 1 revealed:(1)The caregiving stress significantly and negatively predicted coping style(β=−1.18,95%CI[−2.18,−0.18],p<0.01).(2)Caregiving stress also significantly and negatively predicted mindfulness(β=−1.90,95%CI[−2.43,−1.38],p<0.01).(3)Conversely,mindfulness significantly and positively predicted coping style(β=0.85,95%CI[0.62,1.07],p<0.01).These findings suggest that mindfulness mediates the relationship between caregiver burden and coping style.In Study 2,the experimental group showed a significant decrease in caregiver stress post-intervention(t=2.24,p<0.05),a significant increase in mindfulness(t=−4.61,p<0.001),and a significant improvement in coping style(t=−2.36,p<0.01).No significant changes were observed in the control group.Conclusion:MBSR can effectively enhance mindfulness and promote adaptive coping strategies,while reducing caregiver burden among parents of children with leukemia.
基金funded by the Medical University of Lublin,Poland,grant number DS 458.
文摘Objectives Chronic lymphocytic leukemia(CLL)is characterized by progressive immune dysregulation.Invariant natural killer T(iNKT)cells support immune surveillance,but the clinical relevance of their regulatory subsets remains unclear.FoxP3+regulatory iNKT cells(iNKTreg)and E4BP4+IL-10+(iNKT10)cells may reflect immunoregulatory changes associated with disease progression.The study aimed to quantify circulating iNKTreg and iNKT10 subsets and monocytic myeloid-derived suppressor cells(M-MDSCs)in treatment-naïve CLL patients and evaluate their associations with disease characteristics and time to first treatment(TTFT).Methods Peripheral blood samples from 60 untreated CLL patients and 20 healthy donors were analyzed by flow cytometry to determine iNKTreg and iNKT10 percentages,as well as indoleamine 2,3-dioxygenase(IDO)-expressing M-MDSCs.Receiver operating characteristic(ROC)curves and Cox proportional hazards models were used to assess prognostic significance.Results iNKTreg and iNKT10 percentages were significantly increased in CLL compared with healthy donors(p=0.002).Elevated iNKTreg frequencies were associated with zeta-chain-associated protein of 70 kD(ZAP-70)positivity(p=0.017),CD38 positivity(p=0.048),and treatment requirement during follow-up(p=0.016).Based on an ROC-derived cut-off of 9.6%(AUC=0.753),patients with iNKTreg≥9.6%had shorter TTFT(hazard ratio[HR]=2.71;95%confidence interval[CI],1.13–6.49;p=0.025),although the association was not retained in multivariate analysis(HR=1.27;95%CI,0.44–3.64;p=0.626).iNKTreg and iNKT10 percentages correlated positively with IDO+M-MDSCs(p=0.035 and p=0.044),but not with arginase-1(ARG1)or inducible nitric oxide synthase(NOS2).Conclusion Elevated iNKTreg levels reflect a more aggressive disease phenotype and associate with shorter TTFT in univariate analysis,supporting their exploration as complementary immunological biomarkers in CLL.Functional studies and validation in larger cohorts are needed to determine their prognostic and biological significance.
基金supported by grants from the Ministry of Science and Technology,Taiwan(MOST108-2314-B-182-006,MOST109-2314-B-182-071:Lee-Yung Shih)the Ministry of Health and Welfare,Taiwan(MOHW110-TDU-B-212-134011:Lee-Yung Shih)+3 种基金Chang Gung Memorial Hospital(CMRPG3D1524,OMRPG3E0031:Lee-Yung Shih)the Grant-in-Aid for the Japan Society for the Promotion of Science(JSPS)KAKENHI(JP19H05656:Seishi Ogawa,22K16320:Yotaro Ochi)the Japan Agency for Medical Research and Development(AMED)(JP19cm0106501h0004,JP19ck0106250h0003:Seishi Ogawa)the Ministry of Education,Culture,Sports,Science and Technology of Japan(MEXT)(hp200138,hp210167:Seishi Ogawa)。
文摘Background:Breakpoint Cluster Region-Abelson(BCR::ABL1)fusion protein is essential in the pathogenesis of chronic myeloid leukemia(CML);however,the chronic-to-blast phase transformation remains elusive.We identified novel kinesin light chain 2(KLC2)mutations in CML-myeloid blast phase patients.We aimed to examine the functional role of KLC2 mutations in leukemogenesis.Methods:To evaluate the biological role of KLC2 mutants(MT)in CML cells,we expressed KLC2-MT in different human CML cell lines harboring BCR::ABL1 and performed immunoblot,immunofluorescence,cell proliferation,differentiation,and apoptosis;Tyrosine kinase inhibitor(TKI)-drug activities;and clonogenic assays for in vitro functional analyses.We co-expressed KLC2-MT and BCR::ABL1 in mouse bone marrow cells(BMCs)to evaluate their clonogenic and self-renewal abilities ex vivo.Furthermore,we examined tumorigenic activity and drug efficacy in the K562 xenograft model.Results:KLC2-MT overexpression in BCR::ABL1-positive K562 and KU812 CML cells promoted cell proliferation and clonogenic potential,decreased imatinib sensitivity,and reduced apoptosis.Serial colony replating assays revealed that KLC2-MT and BCR::ABL1 co-expression enhanced the self-renewal ability of mouse BMCs with immature morphology.In the K562 xenograft model,KLC2-MT enhanced tumorigenic potential and diminished imatinib efficacy.Further studies reported that KLC2-MT augmented signal transducer and activator of transcription 3(STAT3)activation and nuclear accumulation in imatinib-treated CML cells.KLC2-WT and KLC2-MT interacted with mothers against decapentaplegic homolog 2(SMAD2);however,the latter impaired transforming growth factor-beta(TGF-β)–mediated SMAD2/3 activation while enhancing STAT3 phosphorylation.Conclusions:This study demonstrates the biological and functional importance of KLC2 mutation in CML cells,potentially enabling the development of better treatment strategies for CML patients carrying KLC2 mutations and providing enhanced understanding of the disease progression.
文摘Background Myelodysplastic syndromes (MDSs), also called preleukemias, are a group of myeloid hematopoietic malignant disorders. We studied the transformation of MDS into acute myeloid leukemia (AML).Methods Leukemic transformation in 151 patients with MDS was dynamically followed up. The clinical manifestation, peripheral blood and bone marrow condition, karyotypes, immunophenotypes, response to treatment, and prognosis of AML evolution from MDS (MDS-AML) were also observed.Results During the course of this study, over the past eight years and seven months, 21 (13.91%) of 151 MDS patients progressed to overt leukemia, with a median interval of 5 (1-23) months. There were no significant differences between rates of leukemic transformation in comparison with the refractory anemia (RA), RA with excess of blasts (RAEB), and RAEB in transformation (RAEB-t) patient groups. Transformation occurred either gradually or rapidly. There were five parameters positively correlated to leukemic transformation: under 40 years of age, pancytopenia of 3 lineages, more than 15% blasts in the bone marrow, at least two abnormal karyotypes, and treatment with combined chemotherapy. All of the 21 patients with leukemia suffered from MDS-AML, and most of them were M 2, M 4, or M 5. Two (9.52%) MDS-AML patients developed extramedullary infiltration. Leukopenia was found in 47.62% of these patients. Two thirds of these patients, whose bone marrows were generally hypercellular, suffered from neutropenia. After developing AML, 8 (47.06%) patients developed abnormal karyotypes. High expression of immature myeloid antigens, including CD 33 [(49.83±24.50)%], CD 13 [(36.38±33.84)%], monocytic antigen CD 14 [(38.50±24.60)%], and stem cell marker CD 34 [(34.67±30.59)%], were found on bone marrow mononuclear cells from MDS-AML patients after leukemic transformation. In some cases, lymphoid antigens, such as CD 5, CD 7, CD 9, and CD 19, coexisted with myeloid antigens. A low complete remission rate (31.25%) and a short survival time, with median survival of 6 (1-28) months, were found in patients with MDS-AML treated by induction chemotherapy.Conclusions MDS has a high risk of developing into AML, either gradually or rapidly. Patients with MDS-AML have specific biological characteristics and a worse prognosis.
基金This study was supported by the National Basic Research Program of China （973 Program, No. 2013CB911000） and the National Nature Science Foundation of China （No. 30971602, 81272929）.Acknowledgements： We thank Dr. Chi Zhenfen for help with cell culture.
文摘Background Both in vitro and in vivo data have demonstrated the TGFBI gene functions as a putative tumor suppressor and is frequently downregulated in human tumors of different histological types.The hypermethylation of the TGFBI promoter,as one of the main regulatory mechanisms,is associated with TGFBI silencing.In this study,we used a methylation-specific PCR （MSP） method to evaluate the methylation status of the TGFBI promoter in human leukemias.Methods Real-time RT-PCR and methylation-specific PCR approaches were performed to define the TGFBI expression and promoter methylation in human leukemia call lines and clinical samples.Genomic DNA was isolated from peripheral blood mononuclear cells from leukemia patients,bisulfite-converted,and analyzed by the MSP method.Results Hypermethylation of the TGFBI promoter occurred in leukemia cell lines and demethylation treatment reexpressed TGFBI at a substantially increased level in most of leukemia cell lines tested.Furthermore,a much higher level of CpG island methylation and a significantly lower TGFBI expression were also identified in clinical leukemia samples.Conclusion The results suggest an important role of promoter methylation in regulating TGFBI expression in leukemia,which provides a useful diagnostic marker for clinical management of human leukemias.
文摘Aim:The main goal of this study was to elucidate at the transcript level the tyrosine kinase expression profiles of primary leukemia cells from mixed lineage leukemia 1 gene rearranged(KMT2A/MLL-R+)acute myeloid leukemia(AML)and acute lymphoblastic leukemia(ALL)patients.Methods:We evaluated protein tyrosine kinase(PTK)gene expression profiles of primary leukemic cells in KMT2A/MLL-R+AML and ALL patients using publicly available archived datasets.Results:Our studies provided unprecedented evidence that the genetic signatures of KMT2A/MLL-R+AML and ALL cells are characterized by transcript-level overexpression of specific PTK.In infants,children and adults with KMT2A/MLL-R+ALL,as well as pediatric patients with KMT2A/MLL-R+AML,the gene expression levels for FLT3,BTK,SYK,JAK2/JAK3,as well as several SRC family PTK were differentially amplified.In adults with KMT2A/MLLR+AML,the gene expression levels for SYK,JAK family kinase TYK2,and the SRC family kinases FGR and HCK were differentially amplified.Conclusion:These results provide new insights regarding the clinical potential of small molecule inhibitors of these PTK,many of which are already FDA/EMA-approved for other indications,as components of innovative multimodality treatment platforms against KMT2A/MLL-R+acute leukemias.
基金The project described was supported by the DHHS grant R43CA177067(Uckun FM)from the National Cancer Institute.The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.Uckun FM was also supported in part by DHHS grants P30CA014089,U01-CA-151837,R01CA-154471 and R21-CA-164098(Uckun FM)from the National Cancer Instituteby the V-Foundation,Nautica Triathlon as well as the Ronald McDonald House Charities of Southern California.
文摘Aim:CD22ΔE12 as an oncogenic driver lesion in aggressive and drug-resistant B-precursor acute lymphoblastic leukemia(BPL)cells.The purpose of the present study was to identify the CD22ΔE12-specific signature transcriptome in human BPL cells and evaluate the clinical potential of a nanoscale formulation of CD22ΔE12-siRNA as an RNAi therapeutic against drug-resistant BPL.CD22ΔE12-siRNA nanoparticles significantly improved the event-free survival(EFS)outcome of NOD/SCID(NS)mice challenged with human BPL xenograft cells.Methods:Gene expression and translational bioinformatics methods were applied to examine the expression of the CD22ΔE12-specific signature transcriptome in human BPL cells in subsets of BPL patients.Survival analysis for mice challenged with BPL cells and treated with CD22ΔE12 siRNA was performed using standard methods.Results:Leukemia cells from CD22ΔE12-Tg mice exhibit gene and protein expression profiles consistent with constitutive activation of multiple signaling networks,mimicking the profiles of relapsed BPL patients as well as newly diagnosed high-risk patients with BCR-ABL+/Philadelphia chromosome(Ph)+BPL as well as Ph-like BPL.A nanoscale formulation of CD22ΔE12-siRNA abrogated the in vivo clonogenicity of the leukemia-initiating leukemic cell fraction in xenograft specimens derived from patients with relapsed BPL and significantly improved the EFS outcome of NS mice challenged with drug-resistant human BPL xenograft cells.Conclusion:The CD22-RNAi technology is applicable to all BPL patients both high risk and standard risk.That is because CD22ΔE12 is a characteristic feature of drug-resistant leukemic clones that escape chemotherapy and cause relapse in both high risk and low risk subgroups of patients.The technology therefore has the potential(1)for prevention of relapses by selectively killing the clones that are most likely to escape chemotherapy and cause relapse as well(2)for treatment of relapses in BPL.This research project may also lead to innovative salvage regimens against other forms of CD22ΔE12-positive relapsed B-lineage leukemias and lymphomas.
基金supported by the Beijing Natural Science Foundation(No.Z230016)the National Key Research and Development Program of China(No.2022YFC 2502606)+4 种基金the Major Program of the National Natural Science Foundation of China(No.82293630)the Peking University Medicine Fund for the World’s Leading Discipline or Discipline Cluster Development(No.71003Y3035)the Plan Project of Tongzhou Municipal Science and Technology(No.KJ2024CX045)the National Natural Science Foundation of China(No.82170208)the Fundamental Research Funds for the Central Universities。
文摘Objective:Adverse-risk acute myeloid leukemia(AML)patients should receive allogeneic hematopoietic stem cell transplantation(allo-HSCT)at first complete remission(CR1).However,the influence of prior therapies[i.e.,venetoclax plus azacitidine(VEN-AZA)or intensive chemotherapy(IC)]on post-transplant outcomes remains inconclusive.This multicenter,retrospective study compared the post-transplant outcomes between patients receiving VEN-AZA and those receiving IC before allo-HSCT.Methods:This study was based on the transplant database of TROPHY group.Consecutive adverse-risk AML patients receiving allo-HSCT from January 2021 to June 2023 were screened in five Chinese transplant centers.Patients were categorized into VEN-AZA group if they received venetoclax combined with azacitidine as first-line therapy followed by allo-HSCT.Patients who received first-line therapy consisting of a mainstay treatment of cytarabine and anthracycline followed by allo-HSCT were categorized into IC group.Results:In the total cohort,the 3-year probabilities of overall survival,leukemia-free survival,and event-free survival were better in the IC group than VEN-AZA group,particularly for patients with ASXL1 mutations or SF3B1 mutations.However,the survival of the VEN-AZA group was not superior to that of IC group in patients aged≥55 years or those with the hematopoietic cell transplantation-comorbidity index scores≥1 before allo-HSCT.After propensity score matching(median age:VEN-AZA group:57 years;IC group:55 years),only the probability of overall survival for the IC group was better than that of VEN-AZA group(93.6%vs.78.0%,P=0.034)at the 1-year follow-up;however,all of the other clinical outcomes were comparable between the VEN-AZA and IC groups.The TP53 mutation was independently associated with post-transplant relapse and survival.Conclusions:Our results suggest that IC remains the cornerstone of therapy,whereas VEN-AZA may also be used in younger patients and medically fit patients with adverse-risk AML who are receiving allo-HSCT in CR1.
文摘Patients with leukemia often suffer from the combined effects of cancer-related fatigue(CRF)and subthreshold depression,which mutually exacerbate each other in a vicious cycle.In this editorial,we comment on the article by Liu et al,published in the World Journal of Psychiatry.We further elucidate the profound impact of subthreshold depressive symptoms on the experience of CRF and complications in patients with leukemia.This editorial highlights the importance of early identification and treatment of subclinical depression,and advocates for a multidisciplinary and integrated treatment approach that includes social support,psychological interventions,and individualized treatment plans.Future research needs to explore the biological mechanisms underlying the interaction between the two to develop more effective prevention and treatment strategies.
文摘BACKGROUND Acute myeloid leukemia(AML)is a complicated disease with uncontrolled hematopoietic precursor proliferation induced by various genetic alterations.Runt-related transcription factor-1(RUNX1)is commonly disrupted by chromosomal translocations in hematological malignancies.AIM To characterize RUNX1 gene rearrangements and copy number variations in newly diagnosed adult AML patients,with an emphasis on the impact of clinical and laboratory features on the outcome.METHODS Fluorescence in situ hybridization was used to test RUNX1 gene alterations in 77 newly diagnosed adult AML cases.NPM1,FLT3/ITD,FLT3/TKD,and KIT mutations were tested by PCR.Prognostic clinical and laboratory findings were studied in relation to RUNX1 alterations.RESULTS RUNX1 abnormalities were detected by fluorescence in situ hybridization in 41.6%of patients:20.8%had translocations,22.1%had amplification,and 5.2%had deletion.Translocations prevailed in AML-M2(P=0.019)with a positive expression of myeloperoxidase(P=0.031),whereas deletions dominated in M4 and M5 subtypes(P=0.008)with a positive association with CD64 expression(P=0.05).The modal chromosomal number was higher in cases having amplifications(P=0.007)and lower in those with deletions(P=0.008).RUNX1 abnormalities were associated with complex karyotypes(P<0.001)and were mutually exclusive of NPM1 mutations.After 44 months of follow-up,RUNX1 abnormalities affected neither patients’response to treatment nor overall survival.CONCLUSION RUNX1 abnormalities were mutually exclusive of NPM1 mutations.RUNX1 abnormalities affected neither patients’response to treatment nor overall survival.
