Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Leukemia. 2022 Aug;36(8):2097-2107. doi: 10.1038/s41375-022-01605-1. Epub 2022 Jun 14.
Loss-of-function TET2 mutations are recurrent somatic lesions in chronic myelomonocytic leukemia (CMML). KDM6B encodes a histone demethylase involved in innate immune regulation that is overexpressed in CMML. We conducted genomic and transcriptomic analyses in treatment naïve CMML patients and observed that the patients carrying both TET2 mutations and KDM6B overexpression constituted 18% of the cohort and 42% of patients with TET2 mutations. We therefore hypothesized that KDM6B overexpression cooperated with TET2 deficiency in CMML pathogenesis. We developed a double-lesion mouse model with both aberrations, and discovered that the mice exhibited a more prominent CMML-like phenotype than mice with either Tet2 deficiency or KDM6B overexpression alone. The phenotype includes monocytosis, anemia, splenomegaly, and increased frequencies and repopulating activity of bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs). Significant transcriptional alterations were identified in double-lesion mice, which were associated with activation of proinflammatory signals and repression of signals maintaining genome stability. Finally, KDM6B inhibitor reduced BM repopulating activity of double-lesion mice and tumor burden in mice transplanted with BM-HSPCs from CMML patients with TET2 mutations. These data indicate that TET2 deficiency and KDM6B overexpression cooperate in CMML pathogenesis of and that KDM6B could serve as a potential therapeutic target in this disease.
TET2 功能丧失突变是慢性粒单核细胞白血病（CMML）中反复出现的体细胞病变。KDM6B 编码一种组蛋白去甲基酶，参与先天免疫调节，在 CMML 中过表达。我们对未经治疗的 CMML 患者进行了基因组和转录组分析，观察到同时携带 TET2 突变和 KDM6B 过表达的患者占队列的 18%，占 TET2 突变患者的 42%。因此，我们假设 KDM6B 过表达与 TET2 缺乏在 CMML 发病机制中协同作用。我们开发了一种同时具有这两种异常的双损伤小鼠模型，并发现与单独缺乏 Tet2 或过表达 KDM6B 的小鼠相比，该小鼠表现出更明显的 CMML 样表型。表型包括单核细胞增多症、贫血、脾肿大以及骨髓（BM）造血干细胞和祖细胞（HSPCs）的频率增加和再生成活性增强。在双损伤小鼠中鉴定到显著的转录改变，这些改变与促炎信号的激活和维持基因组稳定性的信号的抑制有关。最后，KDM6B 抑制剂降低了双损伤小鼠 BM 再生成活性，并降低了移植来自携带 TET2 突变的 CMML 患者的 BM-HSPC 的小鼠的肿瘤负担。这些数据表明，TET2 缺乏和 KDM6B 过表达在 CMML 发病机制中协同作用，并且 KDM6B 可以作为该疾病的潜在治疗靶点。
