Acute myeloid leukaemia(AML)patients harbouring certain chromosome abnormalities have particularly adverse prognosis.For these patients,targeted therapies have not yet made a significant clinical impact.To understand ...Acute myeloid leukaemia(AML)patients harbouring certain chromosome abnormalities have particularly adverse prognosis.For these patients,targeted therapies have not yet made a significant clinical impact.To understand the molecular landscape of poor prognosis AML we profiled 74 patients from two different centres(in UK and Finland)at the proteomic,phosphoproteomic and drug response phenotypic levels.These data were complemented with transcriptomics analysis for 39 cases.Data integration highlighted a phosphoproteomics signature that define two biologically distinct groups of KMT2A rearranged leukaemia,which we term MLLGA and MLLGB.MLLGA presented increased DOT1L phosphorylation,HOXA gene expression,CDK1 activity and phosphorylation of proteins involved in RNA metabolism,replication and DNA damage when compared to MLLGB and no KMT2A rearranged samples.MLLGA was particularly sensitive to 15 compounds including genotoxic drugs and inhibitors of mitotic kinases and inosine-5-monosphosphate dehydrogenase(IMPDH)relative to other cases.Intermediate-risk KMT2A-MLLT3 cases were mainly represented in a third group closer to MLLGA than to MLLGB.The expression of IMPDH2 and multiple nucleolar proteins was higher in MLLGA and correlated with the response to IMPDH inhibition in KMT2A rearranged leukaemia,suggesting a role of the nucleolar activity in sensitivity to treatment.In summary,our multilayer molecular profiling of AML with poor prognosis and KMT2A-MLLT3 karyotypes identified a phosphoproteomics signature that defines two biologically and phenotypically distinct groups of KMT2A rearranged leukaemia.These data provide a rationale for the potential development of specific therapies for AML patients characterised by the MLLGA phosphoproteomics signature identified in this study.展开更多
基金We thank Adrian Kontor for technical help with the manipulation of AML primary samples,Sarah Mueller for managing the supply of AML primary samples,Janet Matthews for assisting with the processing of patient clinical data,Ruth Osuntola for technical assistance with the mass spectrometry experiments and the FIMM High Throughput Biomedicine Unit for their expert technical support.This work was mainly funded by Cancer Research UK(C15966/A24375)with additional contribution from Blood Cancer UK(20008).All authors have read and approved the article.
文摘Acute myeloid leukaemia(AML)patients harbouring certain chromosome abnormalities have particularly adverse prognosis.For these patients,targeted therapies have not yet made a significant clinical impact.To understand the molecular landscape of poor prognosis AML we profiled 74 patients from two different centres(in UK and Finland)at the proteomic,phosphoproteomic and drug response phenotypic levels.These data were complemented with transcriptomics analysis for 39 cases.Data integration highlighted a phosphoproteomics signature that define two biologically distinct groups of KMT2A rearranged leukaemia,which we term MLLGA and MLLGB.MLLGA presented increased DOT1L phosphorylation,HOXA gene expression,CDK1 activity and phosphorylation of proteins involved in RNA metabolism,replication and DNA damage when compared to MLLGB and no KMT2A rearranged samples.MLLGA was particularly sensitive to 15 compounds including genotoxic drugs and inhibitors of mitotic kinases and inosine-5-monosphosphate dehydrogenase(IMPDH)relative to other cases.Intermediate-risk KMT2A-MLLT3 cases were mainly represented in a third group closer to MLLGA than to MLLGB.The expression of IMPDH2 and multiple nucleolar proteins was higher in MLLGA and correlated with the response to IMPDH inhibition in KMT2A rearranged leukaemia,suggesting a role of the nucleolar activity in sensitivity to treatment.In summary,our multilayer molecular profiling of AML with poor prognosis and KMT2A-MLLT3 karyotypes identified a phosphoproteomics signature that defines two biologically and phenotypically distinct groups of KMT2A rearranged leukaemia.These data provide a rationale for the potential development of specific therapies for AML patients characterised by the MLLGA phosphoproteomics signature identified in this study.
