ASXL1 mutation frequently occurs in all forms of myeloid malignancies and is associated with aggressive disease and poor prognosis. ASXL1 recruits Polycomb repressive complex 2 (PRC2) to specific gene loci to repress transcription through trimethylation of histone H3 on lysine 27 (H3K27me3). ASXL1 alterations reduce H3K27me3 levels, which results in leukemogenic gene expression and the development of myeloid malignancies. Standard therapies for myeloid malignancies have limited efficacy when mutated ASXL1 is present. We discovered upregulation of lysine demethylase 6B (KDM6B), a demethylase for H3K27me3, in ASXL1-mutant leukemic cells, which further reduces H3K27me3 levels and facilitates myeloid transformation. Here, we demonstrated that heterozygous deletion of Kdm6b restored H3K27me3 levels and normalized dysregulated gene expression in Asxl1^Y588XTg hematopoietic stem/progenitor cells (HSPCs). Furthermore, heterozygous deletion of Kdm6b decreased the HSPC pool, restored their self-renewal capacity, prevented biased myeloid differentiation, and abrogated progression to myeloid malignancies in Asxl1^Y588XTg mice. Importantly, administration of GSK-J4, a KDM6B inhibitor, not only restored H3K27me3 levels but also reduced the disease burden in NSG mice xenografted with human ASXL1-mutant leukemic cells in vivo. This preclinical finding provides compelling evidence that targeting KDM6B may be a therapeutic strategy for myeloid malignancies with ASXL1 mutations.

中文翻译：

---

靶向赖氨酸脱甲基酶 6B 可改善临床前模型中 ASXL1 截短介导的骨髓恶性肿瘤

ASXL1突变经常发生在所有形式的骨髓恶性肿瘤中，并与侵袭性疾病和不良预后相关。ASXL1 将 Polycomb 抑制复合物 2 (PRC2) 招募到特定基因位点，通过组蛋白 H3 在赖氨酸 27 (H3K27me3) 上的三甲基化来抑制转录。ASXL1 的改变会降低 H3K27me3 的水平，从而导致白血病基因表达和骨髓恶性肿瘤的发展。当存在ASXL1突变时，骨髓恶性肿瘤的标准疗法疗效有限。我们发现ASXL1突变白血病细胞中赖氨酸脱甲基酶 6B (KDM6B)（一种 H3K27me3 脱甲基酶）上调，这进一步降低了 H3K27me3 水平并促进骨髓转化。在这里，我们证明Kdm6b的杂合缺失可以恢复Asxl1 ^Y588X Tg 造血干/祖细胞 (HSPC)中的 H3K27me3 水平并使失调的基因表达正常化。此外，Kdm6b的杂合缺失减少了Asxl1 ^Y588X Tg 小鼠的 HSPC 库，恢复了其自我更新能力，防止了偏向的骨髓分化，并消除了向骨髓恶性肿瘤的进展。重要的是，给予 KDM6B 抑制剂 GSK-J4 不仅可以恢复 H3K27me3 水平，还可以减轻体内异种移植人ASXL1突变白血病细胞的 NSG 小鼠的疾病负担。这一临床前发现提供了令人信服的证据，表明靶向 KDM6B 可能是治疗ASXL1突变骨髓恶性肿瘤的一种治疗策略。