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Abstract：
Juvenile myelomonocytic leukemia (JMML) is an aggressive hematopoietic disorder of infancy and early childhood driven by constitutively active RAS signaling and characterized by abnormal proliferation of the granulocytic-monocytic blood cell lineage. Most JMML patients require hematopoietic stem cell transplantation for cure, but the risk of relapse is high for some JMML subtypes. Azacitidine was shown to effectively reduce leukemic burden in a subset of JMML patients. However, variable response rates to azacitidine and the risk of drug resistance highlight the need for novel therapeutic approaches. Since RAS signaling is known to interfere with the intrinsic apoptosis pathway, we combined various BH3 mimetic drugs with azacitidine in our previously established patient-derived xenograft model. We demonstrate that JMML cells require both MCL-1 and BCL-XL for survival, and that these proteins can be effectively targeted by azacitidine and BH3 mimetic combination treatment. In vivo azacitidine acts via downregulation of antiapoptotic MCL-1 and upregulation of proapoptotic BH3-only. The combination of azacitidine with BCL-XL inhibition was superior to BCL-2 inhibition in eliminating JMML cells. Our findings emphasize the need to develop clinically applicable MCL-1 or BCL-XL inhibitors in order to enable novel combination therapies in JMML refractory to standard therapy.
摘要：
幼年型粒单核细胞白血病（JMML）是由组成型活跃的RAS信号传导驱动的婴儿期和早期儿童的侵袭性造血疾病，其特征是粒细胞-单核细胞系的异常增殖。大多数JMML患者需要造血干细胞移植来治愈，但某些JMML亚型的复发风险较高.阿扎胞苷被证明可有效降低JMML患者的白血病负担。然而,阿扎胞苷的不同缓解率和耐药风险凸显了对新型治疗方法的需求.由于已知RAS信号传导会干扰内在的凋亡途径，我们将各种BH3模拟药物与阿扎胞苷联合应用于我们先前建立的患者源性异种移植模型.我们证明JMML细胞需要MCL-1和BCL-XL来存活，阿扎胞苷和BH3模拟物联合治疗可有效靶向这些蛋白。体内阿扎胞苷通过下调抗凋亡MCL-1和仅上调促凋亡BH3起作用。阿扎胞苷与BCL-XL抑制的组合在消除JMML细胞方面优于BCL-2抑制。我们的研究结果强调需要开发临床适用的MCL-1或BCL-XL抑制剂，以便在JMML中实现对标准疗法难治性的新型联合疗法。
