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 的种系单等位基因突变会导致家族性血小板疾病 (RUNX1-FPD)，进而演变成骨髓恶性肿瘤 (FPD-MM)：MDS 或 AML。 FPD-MM 通常在第二个 RUNX1 等位基因和/或其他表观遗传调节因子中存在共突变。在这里，我们利用患者来源的 (PD) FPD-MM 细胞并建立了第一个 FPD-MM AML 细胞系 (GMR-AML1)。 GMR-AML1 细胞表现出 MYB、MYC、BCL2 和 CDK6 的活性超级增强子，增强了 c-Myc、c-Myb、EVI1 和 PLK1 的表达以及 AML 干细胞的表面标志物。在对 FPD-MM 与 RUNX1-FPD 状态患者的骨髓细胞进行纵向研究时，我们证实 FPD-MM 细胞中染色质可及性以及 MYB、MECOM 和 BCL2 的 mRNA 表达增加。 GMR-AML1 和 PD FPD-MM 细胞对高三尖杉酯碱（HHT 或 omacetaxine）或甲苯咪唑诱导的致死敏感，与 c-Myc、EVI1、PLK1、CDK6 和 MCL1 的抑制相关。 MB 和 PLK1 抑制剂 volasertib 联合治疗在 GMR-AML1 细胞中发挥协同体外致死作用。在表达荧光素酶的 GMR-AML1 异种移植模型中，MB、omacetaxine 或 volasertib 单一疗法，或 MB 和 volasertib 联合治疗，显着减轻了免疫衰竭小鼠的 AML 负担并提高了生存率。这些发现突出了 FPD-MM 进展的分子特征，并证明 HHT、MB 和/或 volasertib 是对抗 FPD-MM 细胞模型的有效药物。