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
The Chinese wheat landrace Kaixianluohanmai(KL)expresses the ph-like phenotype.A major QTL,QPh.sicau-3A(syn.phKL),responsible for this effect has been mapped to chromosome arm 3AL.This study presents some characterist...The Chinese wheat landrace Kaixianluohanmai(KL)expresses the ph-like phenotype.A major QTL,QPh.sicau-3A(syn.phKL),responsible for this effect has been mapped to chromosome arm 3AL.This study presents some characteristics of homoeologous pairing and recombination induced by phKL.In KL haploids,the level of homoeologous pairing was elevated relative to Ph1 Chinese Spring(CS)haploids.There was a clear preference for A–D pairing and less frequent for A–B and B–D,reflecting the higher levels of affinity between genomes A and D in wheat.The characteristics of pairing were affected by temperature and magnesium ion supplementation.The suitability of phKL for chromosome engineering was tested on three pairs of homoeologues:2Sv-2B,2Sv-2D,and 2RL-2BL.The recombination rates were 1.68%,0.17%,and 0%,respectively.The phKL locus in KL induced a moderate level of homoeologous chromosome pairing and recombination when the Ph1 locus of wheat was present,both in wheat haploids and hexaploids.The Ph1-imposed criteria for chromosome pairing and crossing over were relaxed to some degree,permitting homoeologous crossing over but only between closely related chromosomes;there was no crossing over between more differentiated chromosomes.Therefore,the phKL system(QPh.sicau-3A)can be a useful tool in chromosome engineering of wheat to transfer genes from closely related species with the benefit of reduced genomic chaos generated by the ph1b mutation.展开更多
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supported by the National Natural Science Foundation of China(31971884,31601300,32172020)USDANIFA(#CA-R-BPS-5411-H)to AJL+1 种基金Natural Science Foundation of Sichuan Province(2022NSFSC1696,2019YJ0415)the National Key Research and Development Program of China(2016YFD0102000)。
文摘The Chinese wheat landrace Kaixianluohanmai(KL)expresses the ph-like phenotype.A major QTL,QPh.sicau-3A(syn.phKL),responsible for this effect has been mapped to chromosome arm 3AL.This study presents some characteristics of homoeologous pairing and recombination induced by phKL.In KL haploids,the level of homoeologous pairing was elevated relative to Ph1 Chinese Spring(CS)haploids.There was a clear preference for A–D pairing and less frequent for A–B and B–D,reflecting the higher levels of affinity between genomes A and D in wheat.The characteristics of pairing were affected by temperature and magnesium ion supplementation.The suitability of phKL for chromosome engineering was tested on three pairs of homoeologues:2Sv-2B,2Sv-2D,and 2RL-2BL.The recombination rates were 1.68%,0.17%,and 0%,respectively.The phKL locus in KL induced a moderate level of homoeologous chromosome pairing and recombination when the Ph1 locus of wheat was present,both in wheat haploids and hexaploids.The Ph1-imposed criteria for chromosome pairing and crossing over were relaxed to some degree,permitting homoeologous crossing over but only between closely related chromosomes;there was no crossing over between more differentiated chromosomes.Therefore,the phKL system(QPh.sicau-3A)can be a useful tool in chromosome engineering of wheat to transfer genes from closely related species with the benefit of reduced genomic chaos generated by the ph1b mutation.
