Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
Blood. 2009 Dec 10;114(25):5201-5. doi: 10.1182/blood-2009-06-223982.
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by proliferation of one or more myeloid cell lineages. Some patients exhibit leukemic transformation (LT) by unknown mechanisms, and chemotherapy may increase the risk of LT. To clarify the molecular mechanisms of LT, gene alterations involved in LT from patients in the chronic phase (CP) of MPNs were identified. Among 18 patients who progressed to leukemia, AML1/RUNX1 mutations were detected in 5 patients at the LT but in none at the CP. To investigate the leukemogenic effect of AML1/RUNX1 mutants, the AML1D171N mutant was transduced into CD34(+) cells from patients in the CP of MPNs. The D171N transduction resulted in proliferation of immature myeloid cells, enhanced self-renewal capacity, and proliferation of primitive progenitors. Taken together, these results indicate that AML1/RUNX1 point mutations may have a leukemogenic potential in MPN stem cells, and they may promote leukemic transformation in MPN.
骨髓增殖性肿瘤（MPN）是一种克隆性造血干细胞疾病，其特征是一种或多种髓系细胞系增殖。一些患者表现出不明机制的白血病转化（LT），而化疗可能会增加 LT 的风险。为了阐明 LT 的分子机制，鉴定了 MPN 慢性期（CP）患者 LT 相关的基因改变。在 18 例进展为白血病的患者中，5 例 LT 患者存在 AML1/RUNX1 突变，但 CP 患者无一例存在。为了研究 AML1/RUNX1 突变体的致白血病作用，将 AML1D171N 突变体转导到 MPN CP 患者的 CD34+细胞中。D171N 转导导致未成熟髓系细胞增殖、自我更新能力增强和原始祖细胞增殖。总之，这些结果表明 AML1/RUNX1 点突变可能在 MPN 干细胞中有潜在的致白血病作用，并且可能促进 MPN 中的白血病转化。
