RUNX1::RUNX1T1急性髓细胞白血病MGA协同突变的功能特征。

Jeffery Klco, Melvin Thomas, Wenqing Qi, Michael Walsh, Jing Ma, Tamara Westover, Sherif Abdelhamed, Lauren Ezzell, Chandra Rolle, Emily Xiong, Wojciech Rosikiewicz, Beisi Xu, Shondra Pruett-Miller, Allister Loughran, Laura Janke
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引用次数: 0

摘要

MGA(Max基因相关)是一种双特异性转录因子,负调控MYC靶基因以抑制增殖和促进分化。MGA的功能缺失突变通常在几种血液肿瘤中被发现,包括患有RUNX1::RUNX1T1的急性髓系白血病(AML),然而,对这些MGA改变对正常造血或疾病进展的影响知之甚少。我们发现,在患者样本中鉴定的代表性MGA突变消除了蛋白质-蛋白质相互作用和转录活性。使用一系列人类和小鼠模型系统,包括新开发的条件敲除小鼠株,我们证明MGA的缺失导致正常造血细胞中MYC和E2F靶点、细胞周期基因、mTOR信号传导和氧化磷酸化的上调,从而导致增殖增强。MGA的缺失在参与细胞周期和增殖的基因的启动子处诱导开放染色质状态。RUNX1::RUNX1T1在Mga缺乏的小鼠造血细胞中的表达导致更具攻击性的AML,潜伏期显著缩短。这些数据表明,MGA调节造血细胞中的多种促增殖途径,并与RUNX1::RUNX1T1融合癌蛋白协同作用以增强白血病的发生。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Functional Characterization of Cooperating MGA Mutations in RUNX1::RUNX1T1 Acute Myeloid Leukemia.

Functional Characterization of Cooperating MGA Mutations in RUNX1::RUNX1T1 Acute Myeloid Leukemia.

Functional Characterization of Cooperating MGA Mutations in RUNX1::RUNX1T1 Acute Myeloid Leukemia.

Functional Characterization of Cooperating MGA Mutations in RUNX1::RUNX1T1 Acute Myeloid Leukemia.

MGA (Max-gene associated) is a dual-specificity transcription factor that negatively regulates MYC-target genes to inhibit proliferation and promote differentiation. Loss-of-function mutations in MGA have been commonly identified in several hematological neoplasms, including acute myeloid leukemia (AML) with RUNX1::RUNX1T1, however, very little is known about the impact of these MGA alterations on normal hematopoiesis or disease progression. We show that representative MGA mutations identified in patient samples abolish protein-protein interactions and transcriptional activity. Using a series of human and mouse model systems, including a newly developed conditional knock-out mouse strain, we demonstrate that loss of MGA results in upregulation of MYC and E2F targets, cell cycle genes, mTOR signaling, and oxidative phosphorylation in normal hematopoietic cells, leading to enhanced proliferation. The loss of MGA induces an open chromatin state at promotors of genes involved in cell cycle and proliferation. RUNX1::RUNX1T1 expression in Mga-deficient murine hematopoietic cells leads to a more aggressive AML with a significantly shortened latency. These data show that MGA regulates multiple pro-proliferative pathways in hematopoietic cells and cooperates with the RUNX1::RUNX1 T1 fusion oncoprotein to enhance leukemogenesis.

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