INSERM U1287, Gustave Roussy Cancer Campus, Villejuif, France.
Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 8590, Université Paris I, Paris, France.
Blood. 2021 Jun 17;137(24):3390-3402. doi: 10.1182/blood.2020008729.
Mouse models of chronic myeloid malignancies suggest that targeting mature cells of the malignant clone disrupts feedback loops that promote disease expansion. Here, we show that in chronic myelomonocytic leukemia (CMML), monocytes that accumulate in the peripheral blood show a decreased propensity to die by apoptosis. BH3 profiling demonstrates their addiction to myeloid cell leukemia-1 (MCL1), which can be targeted with the small molecule inhibitor S63845. RNA sequencing and DNA methylation pattern analysis both point to the implication of the mitogen-activated protein kinase (MAPK) pathway in the resistance of CMML monocytes to death and reveal an autocrine pathway in which the secreted cytokine-like protein 1 (CYTL1) promotes extracellular signal-regulated kinase (ERK) activation through C-C chemokine receptor type 2 (CCR2). Combined MAPK and MCL1 inhibition restores apoptosis of monocytes from patients with CMML and reduces the expansion of patient-derived xenografts in mice. These results show that the combined inhibition of MCL1 and MAPK is a promising approach to slow down CMML progression by inducing leukemic monocyte apoptosis.
慢性髓系恶性肿瘤的小鼠模型表明，靶向恶性克隆的成熟细胞会破坏促进疾病扩张的反馈回路。在这里，我们表明在慢性粒单核细胞白血病（CMML）中，在外周血中积累的单核细胞表现出凋亡减少的倾向。BH3 分析表明它们对髓细胞白血病-1（MCL1）的依赖性，这可以用小分子抑制剂 S63845 靶向。RNA 测序和 DNA 甲基化模式分析都表明丝裂原活化蛋白激酶（MAPK）途径在 CMML 单核细胞对死亡的抵抗中的作用，并揭示了一种自分泌途径，其中细胞因子样蛋白 1（CYTL1）通过 C-C 趋化因子受体 2（CCR2）促进细胞外信号调节激酶（ERK）的激活。联合 MAPK 和 MCL1 抑制恢复了 CMML 患者单核细胞的凋亡，并减少了小鼠中患者来源异种移植物的扩增。这些结果表明，联合抑制 MCL1 和 MAPK 通过诱导白血病单核细胞凋亡是减缓 CMML 进展的一种有前途的方法。
