Department of Haematology.
Department of Genetics, and.
Blood Adv. 2022 Jan 11;6(1):165-180. doi: 10.1182/bloodadvances.2020002842.
Epigenetic histone modifiers are key regulators of cell fate decisions in normal and malignant hematopoiesis. Their enzymatic activities are of particular significance as putative therapeutic targets in leukemia. In contrast, less is known about the contextual role in which those enzymatic activities are exercised and specifically how different macromolecular complexes configure the same enzymatic activity with distinct molecular and cellular consequences. We focus on KAT2A, a lysine acetyltransferase responsible for histone H3 lysine 9 acetylation, which we recently identified as a dependence in acute myeloid leukemia stem cells and that participates in 2 distinct macromolecular complexes: Ada two-A-containing (ATAC) and Spt-Ada-Gcn5-Acetyltransferase (SAGA). Through analysis of human cord blood hematopoietic stem cells and progenitors, and of myeloid leukemia cells, we identify unique respective contributions of the ATAC complex to regulation of biosynthetic activity in undifferentiated self-renewing cells and of the SAGA complex to stabilization or correct progression of cell type-specific programs with putative preservation of cell identity. Cell type and stage-specific dependencies on ATAC and SAGA-regulated programs explain multilevel KAT2A requirements in leukemia and in erythroid lineage specification and development. Importantly, they set a paradigm against which lineage specification and identity can be explored across developmental stem cell systems.
表观遗传组蛋白修饰物是正常和恶性造血中细胞命运决定的关键调节剂。它们的酶活性作为白血病的潜在治疗靶点具有特别重要的意义。相比之下,人们对这些酶活性所发挥的上下文作用知之甚少,特别是不同的大分子复合物如何用不同的分子和细胞后果来配置相同的酶活性。我们专注于 KAT2A,一种负责组蛋白 H3 赖氨酸 9 乙酰化的赖氨酸乙酰转移酶,我们最近将其鉴定为急性髓系白血病干细胞的依赖性,并参与了 2 个不同的大分子复合物:Ada 双 A 包含(ATAC)和 Spt-Ada-Gcn5-乙酰转移酶(SAGA)。通过对人脐带血造血干细胞和祖细胞以及髓样白血病细胞的分析,我们确定了 ATAC 复合物对未分化自我更新细胞中生物合成活性的调节以及 SAGA 复合物对细胞类型特异性程序的稳定性或正确进展的独特各自贡献,而这些程序可能保留了细胞身份。细胞类型和阶段特异性对 ATAC 和 SAGA 调节程序的依赖性解释了白血病以及红细胞谱系特化和发育中多层次 KAT2A 的需求。重要的是,它们为跨发育干细胞系统探索谱系特化和身份提供了一个范例。