Negative effects of GM-CSF signaling in a murine model of t(8;21)-induced leukemia
Negative effects of GM-CSF signaling in a murine model of t(8;21)-induced leukemia
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DOI：
10.1182/blood-2011-04-350694
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发表时间：
2012-03-29
期刊：
影响因子：
20.3
通讯作者：
Zhang, Dong-Er
中科院分区：
文献类型：
--
作者：
Matsuura, Shinobu;Yan, Ming;Zhang, Dong-Er
t(8;21)(q22;q22) 常见于成人急性髓系白血病 (AML)。这种易位表达的 RUNX1-ETO 融合蛋白的致白血病性很差，需要额外的突变才能转化。在 t(8;21) AML 中经常观察到性染色体丢失 (LOS)。在本研究中，为了评估LOS是否与t(8;21)在白血病发生中协同作用，我们首先使用逆转录病毒转导/移植模型在XO小鼠的造血细胞中表达RUNX1-ETO。这些小鼠中白血病的低发生率表明，抑制人类 t(8;21) 白血病的潜在关键基因在小鼠性染色体上并不保守。编码 GM-CSF 受体 α 亚基 (CSF2RA) 的基因位于人类的 X 和 Y 染色体上，但位于小鼠的 19 号染色体上。 GM-CSF 促进骨髓细胞存活、增殖和分化。为了确定 GM-CSF 信号传导是否影响 RUNX1-ETO 白血病发生，使用缺乏 GM-CSF 信号传导的造血干/祖细胞表达 RUNX1-ETO 并移植到接受致命照射的小鼠中，在受者中观察到 AML 的高外显率。此外，GM-CSF 降低了表达 RUNX1-ETO 的细胞的再铺板能力。这些结果表明 GM-CSF 在 RUNX1-ETO 白血病中可能具有肿瘤抑制作用。 CSF2RA 基因的缺失可能是一个关键突变，解释了与 t(8;21)(q22;q22) 易位相关的 LOS 高发生率。 （血。2012；119(13):3155-3163）
The t(8;21)(q22;q22) is common in adult acute myeloid leukemia (AML). The RUNX1-ETO fusion protein that is expressed by this translocation is poorly leukemogenic and requires additional mutations for transformation. Loss of sex chromosome (LOS) is frequently observed in t(8;21) AML. In the present study, to evaluate whether LOS cooperates with t(8;21) in leukemogenesis, we first used a retroviral transduction/transplantation model to express RUNX1-ETO in hematopoietic cells from XO mice. The low frequency of leukemia in these mice suggests that the potentially critical gene for suppression of t(8;21) leukemia in humans is not conserved on mouse sex chromosomes. The gene encoding the GM-CSF receptor alpha subunit (CSF2RA) is located on X and Y chromosomes in humans but on chromosome 19 in mice. GM-CSF promotes myeloid cell survival, proliferation, and differentiation. To determine whether GM-CSF signaling affects RUNX1-ETOleukemogenesis, hematopoietic stem/progenitor cells that lack GM-CSF signaling were used to express RUNX1-ETO and transplanted into lethally irradiated mice, and a high penetrance of AML was observed in recipients. Furthermore, GM-CSF reduced the replating ability of RUNX1-ETO-expressing cells. These results suggest a possible tumor-suppressor role of GM-CSF in RUNX1-ETO leukemia. Loss of the CSF2RA gene may be a critical mutation explaining the high incidence of LOS associated with the t(8;21)(q22;q22) translocation. (Blood. 2012;119(13):3155-3163)