Department of Oncology, Hematology, Immunology, and Rheumatology, University Hospital Tuebingen, 72074 Tuebingen, Germany.
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (IKP), 70376 Stuttgart, Germany.
Cell Stem Cell. 2021 May 6;28(5):906-922.e6. doi: 10.1016/j.stem.2021.03.023. Epub 2021 Apr 23.
Severe congenital neutropenia (CN) is a pre-leukemic bone marrow failure syndrome that can evolve to acute myeloid leukemia (AML). Mutations in CSF3R and RUNX1 are frequently observed in CN patients, although how they drive the transition from CN to AML (CN/AML) is unclear. Here we establish a model of stepwise leukemogenesis in CN/AML using CRISPR-Cas9 gene editing of CN patient-derived iPSCs. We identified BAALC upregulation and resultant phosphorylation of MK2a as a key leukemogenic event. BAALC deletion or treatment with CMPD1, a selective inhibitor of MK2a phosphorylation, blocked proliferation and induced differentiation of primary CN/AML blasts and CN/AML iPSC-derived hematopoietic stem and progenitor cells (HSPCs) without affecting healthy donor or CN iPSC-derived HSPCs. Beyond detailing a useful method for future investigation of stepwise leukemogenesis, this study suggests that targeting BAALC and/or MK2a phosphorylation may prevent leukemogenic transformation or eliminate AML blasts in CN/AML and RUNX1 mutant BAALC(hi) de novo AML.
严重先天性中性粒细胞减少症（CN）是一种前白血病骨髓衰竭综合征，可发展为急性髓系白血病（AML）。CSF3R 和 RUNX1 的突变在 CN 患者中经常观察到，尽管它们如何驱动从 CN 到 AML 的转变（CN/AML）尚不清楚。在这里，我们使用 CN 患者来源的 iPSC 的 CRISPR-Cas9 基因编辑建立了 CN/AML 逐步白血病发生的模型。我们确定了 BAALC 的上调和 MK2a 的磷酸化作为关键的白血病发生事件。BAALC 缺失或 MK2a 磷酸化的选择性抑制剂 CMPD1 的治疗阻断了原发性 CN/AML 原始细胞和 CN/AML iPSC 衍生造血干细胞和祖细胞（HSPC）的增殖，并诱导其分化，而不影响健康供体或 CN iPSC 衍生的 HSPC。除了详细描述未来逐步白血病发生研究的有用方法外，这项研究表明，靶向 BAALC 和/或 MK2a 磷酸化可能预防 CN/AML 和 RUNX1 突变 BAALC(hi) 从头 AML 中的白血病转化或消除 AML 原始细胞。
