Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA.
Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR, 97239, USA.
Nat Commun. 2019 Nov 29;10(1):5455. doi: 10.1038/s41467-019-13364-2.
Acute Myeloid Leukemia (AML) develops due to the acquisition of mutations from multiple functional classes. Here, we demonstrate that activating mutations in the granulocyte colony stimulating factor receptor (CSF3R), cooperate with loss of function mutations in the transcription factor CEBPA to promote acute leukemia development. The interaction between these distinct classes of mutations occurs at the level of myeloid lineage enhancers where mutant CEBPA prevents activation of a subset of differentiation associated enhancers. To confirm this enhancer-dependent mechanism, we demonstrate that CEBPA mutations must occur as the initial event in AML initiation. This improved mechanistic understanding will facilitate therapeutic development targeting the intersection of oncogene cooperativity.
急性髓细胞白血病 (AML) 的发生是由于获得了多个功能类别中的突变。在这里，我们证明粒细胞集落刺激因子受体 (CSF3R) 的激活突变与转录因子 CEBPA 的功能丧失突变协同作用，促进急性白血病的发展。这些不同类别的突变之间的相互作用发生在髓样谱系增强子的水平，突变的 CEBPA 阻止了一组分化相关增强子的激活。为了证实这种增强子依赖的机制，我们证明 CEBPA 突变必须作为 AML 起始的初始事件发生。这种对机制的更好理解将有助于针对致癌基因协同作用的治疗方法的开发。
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