NUP98 fuses with approximately 34 different partner genes via translocation in hematological malignancies. Transgenic or retrovirus-mediated bone marrow transplanted mouse models reveal the leukemogenesis of some NUP9...NUP98 fuses with approximately 34 different partner genes via translocation in hematological malignancies. Transgenic or retrovirus-mediated bone marrow transplanted mouse models reveal the leukemogenesis of some NUP98-related fusion genes. We previously reported the fusion protein NUP98-IQ motif containing G （IQCG） in a myeloid/T lymphoid bi-phenoleukemia patient with t（3;11） and confirmed its leukemogenic ability. Herein, we demonstrated the association of NUP98-IQCG with CRM1, and found that NUP98-IQCG expression inhibits the CRMl-mediated nuclear export of p65 and enhances the transcriptional activity of nuclear factor-κB. Moreover, IQCG could be entrapped in the nucleus by NUP98-IQCG, and the fusion protein interacts with calmodulin via the IQ motif in a calcium-independent manner. Therefore, the inhibition of nuclear exports of p65 and IQCG might contribute to the leukemogenesis of NUP98-IQCG.展开更多
Chimeric antigen receptor T-cell(CAR-T)therapy has been successfully applied in clinical treatment,especially for hematologic malignancies such as multiple myeloma(MM),but its broad application is limited by cytokine ...Chimeric antigen receptor T-cell(CAR-T)therapy has been successfully applied in clinical treatment,especially for hematologic malignancies such as multiple myeloma(MM),but its broad application is limited by cytokine release syndrome(CRS),a potentially life-threatening complication.Although metabolic alterations are known to accompany CRS,predictive biomarkers for its onset,severity,and associated metabolic remodeling remain unknown,hindering proactive clinical management.Here,we analyzed longitudinal serum metabolic profiles from 19 patients with relapsed/refractory MM receiving CAR-T therapy,with validation in an independent cohort of 23 patients.We observed dysregulated arginine metabolism that progressed alongside clinical CRS.At pre-lymphodepletion(Day–5),over half of differentially abundant metabolites were enriched in unsaturated fatty acid(UFA)synthesis pathways,which were exclusively upregulated in patients who later developed severe CRS.Furthermore,two lysophosphatidylcholines,namely,lysoPC(16:0)and lysoPC(15:0),were significantly associated with delayed CRS onset,with elevated concentrations correlated with a prolonged time to onset;this association was independently validated.These findings revealed that arginine metabolism was a pathological axis in CRS,UFAs were severity predictors,and specific lysoPCs were modulators of onset time.Collectively,they provide proactive CRS management,addressing critical gaps in predictive biomarkers to advance the safe,broad CAR-T application in MM.展开更多
基金This work was supported by the National Basic Research Program of China （No. 2013CB966800）, Ministry of Health （No.201202003）, the Mega-projects of Scientific Research for the 12th Five-Year Plan （No. 2013ZX09303302）, the State Key Laboratories Project ofExcellence （No. 81123005）, the National Natural Science Foundation of China （Nos. 81222004 and 81170506）, and the Samuel Waxman Cancer Research Foundation Co-PI Program.
文摘NUP98 fuses with approximately 34 different partner genes via translocation in hematological malignancies. Transgenic or retrovirus-mediated bone marrow transplanted mouse models reveal the leukemogenesis of some NUP98-related fusion genes. We previously reported the fusion protein NUP98-IQ motif containing G （IQCG） in a myeloid/T lymphoid bi-phenoleukemia patient with t（3;11） and confirmed its leukemogenic ability. Herein, we demonstrated the association of NUP98-IQCG with CRM1, and found that NUP98-IQCG expression inhibits the CRMl-mediated nuclear export of p65 and enhances the transcriptional activity of nuclear factor-κB. Moreover, IQCG could be entrapped in the nucleus by NUP98-IQCG, and the fusion protein interacts with calmodulin via the IQ motif in a calcium-independent manner. Therefore, the inhibition of nuclear exports of p65 and IQCG might contribute to the leukemogenesis of NUP98-IQCG.
基金supported by the State Key Laboratory of Medical Genomics,the Double First-Class Project(No.WF510162602)from the Ministry of EducationOverseas Expertise Introduction Project for Discipline Innovation(111 Project,No.B17029)+2 种基金National Natural Science Foundation of China(Nos.82230006,82470206,32170663,32470681,and 81770124)Innovative Research Team of High-level Local Universities in Shanghai and CAMS Innovation Fund for Medical Sciences(No.CIFMS 2021-I2M-5-010)Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support(No.RC20210190).
文摘Chimeric antigen receptor T-cell(CAR-T)therapy has been successfully applied in clinical treatment,especially for hematologic malignancies such as multiple myeloma(MM),but its broad application is limited by cytokine release syndrome(CRS),a potentially life-threatening complication.Although metabolic alterations are known to accompany CRS,predictive biomarkers for its onset,severity,and associated metabolic remodeling remain unknown,hindering proactive clinical management.Here,we analyzed longitudinal serum metabolic profiles from 19 patients with relapsed/refractory MM receiving CAR-T therapy,with validation in an independent cohort of 23 patients.We observed dysregulated arginine metabolism that progressed alongside clinical CRS.At pre-lymphodepletion(Day–5),over half of differentially abundant metabolites were enriched in unsaturated fatty acid(UFA)synthesis pathways,which were exclusively upregulated in patients who later developed severe CRS.Furthermore,two lysophosphatidylcholines,namely,lysoPC(16:0)and lysoPC(15:0),were significantly associated with delayed CRS onset,with elevated concentrations correlated with a prolonged time to onset;this association was independently validated.These findings revealed that arginine metabolism was a pathological axis in CRS,UFAs were severity predictors,and specific lysoPCs were modulators of onset time.Collectively,they provide proactive CRS management,addressing critical gaps in predictive biomarkers to advance the safe,broad CAR-T application in MM.
