在慢性淋巴细胞白血病（CLL）中，表观遗传变化被认为是中央形成推动疾病演变和基础生物学及临床亚型的转录标记的因素。CLL中还没有对表观遗传调节因子，尤其是组蛋白修饰酶的表征。为了建立与CLL相关的癌基因T细胞白血病1A（TCL1A）的作用器，我们发现在B细胞中，Lysine-specific组蛋白去甲基化酶KDM1A与TCL1A蛋白相互作用，并且KDM1A的催化活性增加。我们证明了KDM1A在恶性B细胞中被上调。升高的KDM1A和相关的基因表达标志物与侵袭性疾病特征和不良临床结果在大型前瞻性CLL试验队列中相关。在Eμ-TCL1A小鼠中遗传Kdm1a的敲低（Kdm1a-KD）降低了白血病负担并延长了动物生存时间，并伴随上调的p53和促凋亡通路。遗传KDM1A空泛还影响了环境组分（T细胞、基质、单核细胞），导致它们支持CLL细胞生存和增殖的能力显着降低。对Eµ-TCL1A与iKdm1aKD;Eµ-TCL1A小鼠的差异全局转录组（RNA-seq）和H3K4me3标记（ChIP-seq）进行的综合分析（在人类CLL中确认）提示KDM1A通过改变组蛋白甲基化模式，在CLL中作为致癌的转录抑制因子，在明确的细胞死亡和运动途径上产生重要的作用。最后，药物学上的KDM1A抑制改变了H3K4/9目标的甲基化，并显示了明显的抗B细胞白血病协同作用。总的来说，我们在CLL中建立了KDM1A的致病作用和作用网络，即通过肿瘤细胞内在机制和对微环境中的细胞的影响。我们的数据也提供了进一步研究CLL中治疗KDM1A的靶向的合理性。Copyright © 2023美国血液学会。

In chronic lymphocytic leukemia (CLL), epigenetic alterations are considered to centrally shape the transcriptional signatures that drive disease evolution and that underlie its biological and clinical subsets. Characterizations of epigenetic regulators, particularly histone-modifying enzymes, are very rudimentary in CLL. In efforts to establish effectors of the CLL-associated oncogene T-cell leukemia 1A (TCL1A), we identified here the lysine-specific histone demethylase KDM1A to interact with the TCL1A protein in B-cells in conjunction with an increased catalytic activity of KDM1A. We demonstrate that KDM1A is upregulated in malignant B-cells. Elevated KDM1A and associated gene expression signatures correlated with aggressive disease features and adverse clinical outcomes in a large prospective CLL trial cohort. Genetic Kdm1a knockdown (Kdm1a-KD) in Eμ-TCL1A mice reduced leukemic burden and prolonged animal survival, accompanied by upregulated p53 and pro-apoptotic pathways. Genetic KDM1A depletion also affected milieu components (T-, stromal, monocytic cells), resulting in significant reductions of their capacity to support CLL cell survival and proliferation. Integrated analyses of differential global transcriptomes (RNA-seq) and H3K4me3 marks (ChIP-seq) in Eµ-TCL1A vs. iKdm1aKD;Eµ-TCL1A mice (confirmed in human CLL) implicate KDM1A as an oncogenic transcriptional repressor in CLL by altering histone methylation patterns with pronounced effects on defined cell death and motility pathways. Finally, pharmacologic KDM1A inhibition altered H3K4/9 target methylation and revealed marked anti-B-cell-leukemic synergisms. Overall, we established the pathogenic role and effector networks of KDM1A in CLL, namely via tumor-cell intrinsic mechanisms and impacts in cells of the microenvironment. Our data also provide rationales to further investigate therapeutic KDM1A targeting in CLL.Copyright © 2023 American Society of Hematology.