Integrative phosphoproteomics defines two biologically distinct groups of KMT2A rearranged acute myeloid leukaemia with different drug response phenotypes.
Integrative phosphoproteomics defines two biologically distinct groups of KMT2A rearranged acute myeloid leukaemia with different drug response phenotypes.
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DOI：
10.1038/s41392-022-01288-1
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发表时间：
2023-02-27
影响因子：
39.3
通讯作者：
Cutillas, Pedro R.
中科院分区：
文献类型：
--
作者：
Casado, Pedro;Rio-Machin, Ana;Miettinen, Juho J.;Bewicke-Copley, Findlay;Rouault-Pierre, Kevin;Krizsan, Szilvia;Parsons, Alun;Rajeeve, Vinothini;Miraki-Moud, Farideh;Taussig, David C.;Boedoer, Csaba;Gribben, John;Heckman, Caroline;Fitzgibbon, Jude;Cutillas, Pedro R.
携带某些染色体异常的急性髓性白血病（AML）患者具有特别不利的预后。对于这些患者，靶向治疗尚未产生显著的临床影响。为了了解预后不良AML的分子景观，我们在蛋白质组学、磷酸化蛋白质组学和药物反应表型水平上对来自两个不同中心（英国和芬兰）的74例患者进行了分析。这些数据与39例病例的转录组学分析相补充。数据整合突出了磷酸蛋白质组学特征，该特征定义了两组生物学上不同的KMT 2A重排白血病，我们称之为MLLGA和MLLGB。与MLLGB和无KMT 2A重排的样品相比，MLLGA呈现增加的DOT 1 L磷酸化、HOXA基因表达、CDK 1活性和参与RNA代谢、复制和DNA损伤的蛋白质的磷酸化。MLLGA是特别敏感的15种化合物，包括遗传毒性药物和有丝分裂激酶和肌苷-5-单磷酸脱氢酶（IMPDH）相对于其他情况下的抑制剂。中等风险KMT 2A-MLLT 3病例主要出现在第三组，更接近MLLGA而不是MLLGB。IMPDH 2和多种核仁蛋白的表达在MLLGA中较高，并且与KMT 2A重排白血病中对IMPDH抑制的反应相关，表明核仁活性在对治疗的敏感性中的作用。总之，我们对预后不良的AML和KMT 2A-MLLT 3核型的多层分子分析鉴定了磷酸蛋白质组学特征，其定义了两组生物学和表型不同的KMT 2A重排白血病。这些数据为针对AML患者的特异性治疗的潜在开发提供了依据，AML患者的特征在于本研究中鉴定的MLLGA磷酸蛋白质组学特征。
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.
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