Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
Nat Commun. 2021 Feb 16;12(1):1054. doi: 10.1038/s41467-021-21233-0.
In acute myeloid leukemia (AML), molecular heterogeneity across patients constitutes a major challenge for prognosis and therapy. AML with NPM1 mutation is a distinct genetic entity in the revised World Health Organization classification. However, differing patterns of co-mutation and response to therapy within this group necessitate further stratification. Here we report two distinct subtypes within NPM1 mutated AML patients, which we label as primitive and committed based on the respective presence or absence of a stem cell signature. Using gene expression (RNA-seq), epigenomic (ATAC-seq) and immunophenotyping (CyToF) analysis, we associate each subtype with specific molecular characteristics, disease differentiation state and patient survival. Using ex vivo drug sensitivity profiling, we show a differential drug response of the subtypes to specific kinase inhibitors, irrespective of the FLT3-ITD status. Differential drug responses of the primitive and committed subtype are validated in an independent AML cohort. Our results highlight heterogeneity among NPM1 mutated AML patient samples based on stemness and suggest that the addition of kinase inhibitors to the treatment of cases with the primitive signature, lacking FLT3-ITD, could have therapeutic benefit.
在急性髓系白血病 (AML) 中，患者之间的分子异质性对预后和治疗构成了重大挑战。在修订后的世界卫生组织分类中，具有 NPM1 突变的 AML 是一种独特的遗传实体。然而，该组内不同的共突变模式和对治疗的反应需要进一步分层。在这里，我们报告了 NPM1 突变的 AML 患者中的两种不同亚型，我们根据各自存在或不存在干细胞特征将其标记为原始和定向。通过基因表达 (RNA-seq)、表观基因组 (ATAC-seq) 和免疫表型 (CyToF) 分析，我们将每种亚型与特定的分子特征、疾病分化状态和患者生存联系起来。通过体外药物敏感性分析，我们显示了两种亚型对特定激酶抑制剂的不同药物反应，而与 FLT3-ITD 状态无关。原始和定向亚型的差异药物反应在独立的 AML 队列中得到验证。我们的结果突出了基于干性的 NPM1 突变 AML 患者样本之间的异质性，并表明在缺乏 FLT3-ITD 的情况下，在具有原始特征的病例中添加激酶抑制剂治疗可能具有治疗益处。
