Genetic and epigenetic evolution as a contributor to WT1-mutant leukemogenesis

Genetic studies have identified recurrent somatic mutations in Acute Myeloid Leukemia (AML) patients, including in WT1 (Wilms’ tumor gene 1). The molecular mechanisms by which WT1 mutations contribute to leukemogenesis have not yet been fully elucidated. We investigated the role of Wt1 gene dosage in steady state and pathologic hematopoiesis. Wt1 heterozygous loss enhanced stem cell self-renewal in an age-dependent manner, with increased stem cell function over time and age-dependent leukemic transformation. Wt1-haploinsufficient leukemias were characterized by progressive genetic and epigenetic alterations, including in known leukemia disease alleles, demonstrating a requirement for additional events to promote hematopoietic transformation. Consistent with this observation, we found that Wt1 haploinsufficiency cooperates with Flt3-ITD mutation to induce fully penetrant AML. Our studies provide insight into mechanisms of Wt1-loss in leukemogenesis and into the evolutionary events required to induce transformation of Wt1-haploinsufficient stem/progenitor cells.遗传学研究已在急性髓系白血病（Acute Myeloid Leukemia, AML）患者中发现了频发的体细胞突变，其中包括WT1（Wilms瘤基因1，Wilms’ tumor gene 1）的突变。WT1突变促发白血病发生的分子机制目前尚未完全阐明。本研究探讨了Wt1基因剂量在稳态造血与病理性造血中的作用。Wt1杂合缺失会以年龄依赖的方式增强干细胞自我更新能力，随时间推移干细胞功能提升，并出现年龄依赖性的白血病转化。Wt1单倍体不足型白血病以进行性遗传与表观遗传改变为特征，涉及已知的白血病疾病等位基因，这表明需要额外的事件来促进造血转化。与该观察结果一致，本研究发现Wt1单倍体不足与Flt3-ITD突变协同可诱导完全外显的AML。本研究为Wt1缺失促发白血病发生的机制，以及诱导Wt1单倍体不足型干/祖细胞转化所需的演化事件提供了新的见解。