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德国图宾根大学Julia Skokowa课题组发现，BAALC是严重先天性中性粒细胞减少症的关键致癌基因。2021年4月23日，《细胞—干细胞》杂志在线发表了这项成果。

据研究人员介绍，严重的先天性中性粒细胞减少症（CN）是一种白血病前的骨髓衰竭综合征，可发展为急性髓细胞性白血病（AML）。尽管尚不清楚经常在CN患者中观察到的CSF3R和RUNX1突变如何驱动从CN向AML（CN/AML）的转变。

研究人员使用来自CN患者iPSC的CRISPR-Cas9基因编辑建立了CN/AML中逐步的白血病发生模型。研究人员发现，BAALC上调和MK2a的磷酸化是关键的致白血病事件。BAALC缺失或用CMPD1（MK2a磷酸化的选择性抑制剂）进行治疗，可阻断原代CN/AML母细胞和CN/AML iPSC衍生的造血干细胞和祖细胞（HSPC）的增殖并诱导分化，而不会影响健康的供体或CN iPSC衍生的HSPC 。除了详细介绍了这个研究白血病的有用方法外，这项研究还表明，靶向BAALC和/或MK2a磷酸化可能会在CN/AML和RUNX1突变BAALC（hi）的从头AML中阻止白血病的转化或消除AML blast细胞。

附：英文原文

Title: iPSC modeling of stage-specific leukemogenesis reveals BAALC as a key oncogene in severe congenital neutropenia

Author: Benjamin Dannenmann, Maksim Klimiankou, Benedikt Oswald, Anna Solovyeva, Jehan Mardan, Masoud Nasri, Malte Ritter, Azadeh Zahabi, Patricia Arreba-Tutusaus, Perihan Mir, Frederic Stein, Siarhei Kandabarau, Nico Lachmann, Thomas Moritz, Tatsuya Morishima, Martina Konantz, Claudia Lengerke, Tim Ripperger, Doris Steinemann, Miriam Erlacher, Charlotte M. Niemeyer, Cornelia Zeidler, Karl Welte, Julia Skokowa

Issue&Volume: 2021-04-23

Abstract: Severe congenital neutropenia (CN) is a pre-leukemic bone marrow failure syndromethat can evolve to acute myeloid leukemia (AML). Mutations in CSF3R and RUNX1 are frequently observed in CN patients, although how they drive the transition fromCN to AML (CN/AML) is unclear. Here we establish a model of stepwise leukemogenesisin CN/AML using CRISPR-Cas9 gene editing of CN patient-derived iPSCs. We identifiedBAALC 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/AMLiPSC-derived hematopoietic stem and progenitor cells (HSPCs) without affecting healthydonor or CN iPSC-derived HSPCs. Beyond detailing a useful method for future investigationof stepwise leukemogenesis, this study suggests that targeting BAALC and/or MK2a phosphorylationmay prevent leukemogenic transformation or eliminate AML blasts in CN/AML and RUNX1 mutant BAALC(hi) de novo AML.

DOI: 10.1016/j.stem.2021.03.023

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00156-9

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