Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Nat Commun. 2020 Mar 16;11(1):1406. doi: 10.1038/s41467-020-15221-z.
Chromatin organization is a highly orchestrated process that influences gene expression, in part by modulating access of regulatory factors to DNA and nucleosomes. Here, we report that the chromatin accessibility regulator HMGN1, a target of recurrent DNA copy gains in leukemia, controls myeloid differentiation. HMGN1 amplification is associated with increased accessibility, expression, and histone H3K27 acetylation of loci important for hematopoietic stem cells (HSCs) and leukemia, such as HoxA cluster genes. In vivo, HMGN1 overexpression is linked to decreased quiescence and increased HSC activity in bone marrow transplantation. HMGN1 overexpression also cooperates with the AML-ETO9a fusion oncoprotein to impair myeloid differentiation and enhance leukemia stem cell (LSC) activity. Inhibition of histone acetyltransferases CBP/p300 relieves the HMGN1-associated differentiation block. These data nominate factors that modulate chromatin accessibility as regulators of HSCs and LSCs, and suggest that targeting HMGN1 or its downstream effects on histone acetylation could be therapeutically active in AML.
染色质组织是一个高度协调的过程，它通过调节调节因子对 DNA 和核小体的访问来影响基因表达。在这里，我们报告说染色质可及性调节剂 HMGN1 是白血病中反复出现的 DNA 拷贝增加的靶标，它控制着髓样分化。HMGN1 扩增与造血干细胞 (HSCs) 和白血病中重要基因座的可及性、表达和组蛋白 H3K27 乙酰化增加有关，例如 HoxA 基因簇。在体内，HMGN1 的过表达与骨髓移植中静止期减少和 HSC 活性增加有关。HMGN1 的过表达还与 AML-ETO9a 融合致癌蛋白协同作用，损害髓样分化并增强白血病干细胞 (LSC) 活性。组蛋白乙酰转移酶 CBP/p300 的抑制可缓解 HMGN1 相关的分化阻滞。这些数据将调节染色质可及性的因素作为 HSCs 和 LSCs 的调节剂提名，并表明靶向 HMGN1 或其对组蛋白乙酰化的下游影响在 AML 中可能具有治疗活性。
