Division of Hematology, Department of Internal Medicine, Mayo Clinic, MN, USA.
Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, MN, USA.
Nat Commun. 2021 May 18;12(1):2901. doi: 10.1038/s41467-021-23186-w.
Proliferative chronic myelomonocytic leukemia (pCMML), an aggressive CMML subtype, is associated with dismal outcomes. RAS pathway mutations, mainly NRAS, define the pCMML phenotype as demonstrated by our exome sequencing, progenitor colony assays and a Vav-Cre-Nras mouse model. Further, these mutations promote CMML transformation to acute myeloid leukemia. Using a multiomics platform and biochemical and molecular studies we show that in pCMML RAS pathway mutations are associated with a unique gene expression profile enriched in mitotic kinases such as polo-like kinase 1 (PLK1). PLK1 transcript levels are shown to be regulated by an unmutated lysine methyl-transferase (KMT2A) resulting in increased promoter monomethylation of lysine 4 of histone 3. Pharmacologic inhibition of PLK1 in RAS mutant patient-derived xenografts, demonstrates the utility of personalized biomarker-driven therapeutics in pCMML.
增殖性慢性髓单核细胞白血病（pCMML）是一种侵袭性 CMML 亚型，预后不良。我们的外显子组测序、祖细胞集落测定和 Vav-Cre-Nras 小鼠模型表明，RAS 通路突变，主要是 NRAS，定义了 pCMML 表型。此外，这些突变促进 CMML 向急性髓系白血病转化。通过多组学平台以及生化和分子研究，我们表明在 pCMML 中，RAS 通路突变与一个独特的基因表达谱相关，该表达谱富含有丝分裂激酶，如 Polo 样激酶 1（PLK1）。PLK1 转录本水平受未突变的赖氨酸甲基转移酶（KMT2A）调控，导致组蛋白 H3 赖氨酸 4 的启动子单甲基化增加。在 RAS 突变患者来源的异种移植物中，PLK1 的药理学抑制表明在 pCMML 中，个性化生物标志物驱动的治疗具有实用性。
Zotero 插件
