Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors co-mutations in the second RUNX1 allele and/or other epigenetic regulators. Here we utilized patient-derived (PD) FPD-MM cells and established the first FPD-MM AML cell line (GMR-AML1). GMR-AML1 cells exhibited active super-enhancers of MYB, MYC, BCL2 and CDK6, augmented expressions of c-Myc, c-Myb, EVI1 and PLK1 and surface markers of AML stem cells. In longitudinally studied bone marrow cells from a patient at FPD-MM vs RUNX1-FPD state, we confirmed increased chromatin accessibility and mRNA expressions of MYB, MECOM and BCL2 in FPD-MM cells. GMR-AML1 and PD FPD-MM cells were sensitive to homoharringtonine (HHT or omacetaxine) or mebendazole-induced lethality, associated with repression of c-Myc, EVI1, PLK1, CDK6 and MCL1. Co-treatment with MB and the PLK1 inhibitor volasertib exerted synergistic in vitro lethality in GMR-AML1 cells. In luciferase-expressing GMR-AML1 xenograft model, MB, omacetaxine or volasertib monotherapy, or co-treatment with MB and volasertib, significantly reduced AML burden and improved survival in the immune-depleted mice. These findings highlight the molecular features of FPD-MM progression and demonstrate HHT, MB and/or volasertib as effective agents against cellular models of FPD-MM.
RUNX1基因的种系单等位基因突变会导致家族性血小板疾病（RUNX1-FPD），并可进展为髓系恶性肿瘤（FPD-MM），即骨髓增生异常综合征（MDS）或急性髓系白血病（AML）。FPD-MM通常伴有第二个RUNX1等位基因和/或其他表观遗传调控因子的共突变。本研究利用源自患者（PD）的FPD-MM细胞，建立了首个FPD-MM AML细胞系（GMR-AML1）。GMR-AML1细胞表现出MYB、MYC、BCL2和CDK6的活跃超级增强子，c-Myc、c-Myb、EVI1和PLK1表达增强，并呈现AML干细胞表面标志物。通过对同一患者处于FPD-MM状态与RUNX1-FPD状态的骨髓细胞进行纵向研究，我们证实FPD-MM细胞中MYB、MECOM和BCL2的染色质可及性与mRNA表达均有所增加。GMR-AML1及PD FPD-MM细胞对高三尖杉酯碱（HHT或奥马赛他辛）或甲苯咪唑诱导的细胞死亡具有敏感性，该过程与c-Myc、EVI1、PLK1、CDK6和MCL1的抑制相关。甲苯咪唑与PLK1抑制剂沃拉塞替联合处理在体外对GMR-AML1细胞产生协同致死效应。在表达荧光素酶的GMR-AML1异种移植模型中，单用甲苯咪唑、奥马赛他辛或沃拉塞替，或甲苯咪唑与沃拉塞替联合治疗，均能显著降低免疫缺陷小鼠的AML负荷并延长其生存期。这些发现揭示了FPD-MM进展的分子特征，并证明高三尖杉酯碱、甲苯咪唑和/或沃拉塞替可作为对抗FPD-MM细胞模型的有效制剂。
肿瘤(癌症)患者之家