Department of Pediatrics, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
Department of Genetics, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
Cell Rep. 2024 Aug 27;43(8):114542. doi: 10.1016/j.celrep.2024.114542. Epub 2024 Jul 23.
Granulocyte colony-stimulating factor (G-CSF) is widely used to enhance myeloid recovery after chemotherapy and to mobilize hematopoietic stem cells (HSCs) for transplantation. Unfortunately, through the course of chemotherapy, cancer patients can acquire leukemogenic mutations that cause therapy-related myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). This raises the question of whether therapeutic G-CSF might potentiate therapy-related MDS/AML by disproportionately stimulating mutant HSCs and other myeloid progenitors. A common mutation in therapy-related MDS/AML involves chromosome 7 deletions that inactivate many tumor suppressor genes, including KMT2C. Here, we show that Kmt2c deletions hypersensitize murine HSCs and myeloid progenitors to G-CSF, as evidenced by increased HSC mobilization and enhanced granulocyte production from granulocyte-monocyte progenitors (GMPs). Furthermore, Kmt2c attenuates the G-CSF response independently from its SET methyltransferase function. Altogether, the data raise concerns that monosomy 7 can hypersensitize progenitors to G-CSF, such that clinical use of G-CSF may amplify the risk of therapy-related MDS/AML.
粒细胞集落刺激因子（G-CSF）被广泛用于增强化疗后的骨髓恢复，并动员造血干细胞（HSCs）进行移植。不幸的是，在化疗过程中，癌症患者可能会获得导致治疗相关骨髓增生异常综合征（MDS）或急性髓系白血病（AML）的白血病发生突变。这就提出了一个问题，即治疗性 G-CSF 是否可能通过不成比例地刺激突变的 HSCs 和其他髓样祖细胞来增强治疗相关的 MDS/AML。治疗相关 MDS/AML 中的常见突变涉及 7 号染色体缺失，该缺失使许多肿瘤抑制基因失活，包括 KMT2C。在这里，我们表明 Kmt2c 缺失使小鼠 HSCs 和髓样祖细胞对 G-CSF 敏感，这表现在 HSC 动员增加和粒细胞单核细胞祖细胞（GMP）中粒细胞产生增强。此外，Kmt2c 独立于其 SET 甲基转移酶功能减弱 G-CSF 反应。总之，这些数据引起了人们的关注，即单体 7 可能使祖细胞对 G-CSF 敏感，使得 G-CSF 的临床应用可能会放大治疗相关 MDS/AML 的风险。
