Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.
Exp Hematol. 2014 May;42(5):369-379.e3. doi: 10.1016/j.exphem.2014.01.009. Epub 2014 Jan 31.
We have previously shown that elevated expression of Hairy enhancer of split 1 (Hes1) contributes to blast crisis transition in Bcr-Abl-positive chronic myelogenous leukemia. Here we investigate whether Hes1 is involved in the development of other myeloid neoplasms. Notably, Hes1 expression was elevated in only a few cases of 65 samples with different types of myeloid neoplasms. Interestingly, elevated expression of Hes1 was found in two of five samples of Fip1-like1 platelet-derived growth factor receptor-α (FIP1L1-PDGFA)-positive myeloid neoplasms associated with eosinophilia. Whereas FIP1L1-PDGFRα alone induced acute T-cell leukemia or myeloproliferative neoplasms in mouse bone marrow transplantation models, mice transplanted with bone marrow cells expressing both Hes1 and FIP1L1-PDGFRα developed acute leukemia characterized by an expansion of myeloid blasts and leukemic cells without eosinophilic granules. FIP1L1-PDGFRα conferred cytokine-independent growth to Hes1-transduced common myeloid progenitors, interleukin-3-dependent cells. Imatinib inhibited the growth of common myeloid progenitors expressing Hes1 with FIP1L1-PDGFRα, but not with imatinib-resistant FIP1L1-PDGFRα mutants harboring T674I or D842V. In contrast, ponatinib efficiently eradicated leukemic cells expressing Hes1 and the imatinib-resistant FLP1L1-PDGFRΑ mutant in vitro and in vivo. Thus, we have established mouse models of FIP1L1-PDGFRA-positive leukemia in myeloid blast crisis, which will help elucidate the pathogenesis of the disease and develop a new treatment for it.
我们之前已经表明，Hairy enhancer of split 1（Hes1）的高表达导致 Bcr-Abl 阳性慢性髓系白血病向急变期过渡。在这里，我们研究了 Hes1 是否参与了其他髓系肿瘤的发生。值得注意的是，在 65 例不同类型髓系肿瘤样本中，仅有少数样本的 Hes1 表达升高。有趣的是，在 5 例 Fip1-like1 血小板衍生生长因子受体-α（FIP1L1-PDGFA）阳性伴嗜酸性粒细胞增多的髓系肿瘤样本中，发现 Hes1 表达升高。虽然 FIP1L1-PDGFRα 单独在小鼠骨髓移植模型中诱导急性 T 细胞白血病或骨髓增生性肿瘤，但在表达 Hes1 和 FIP1L1-PDGFRα 的骨髓细胞移植的小鼠中，发展为特征为髓性母细胞和白血病细胞扩增而无嗜酸性粒细胞颗粒的急性白血病。FIP1L1-PDGFRα 赋予 Hes1 转导的共同髓系祖细胞、白细胞介素-3 依赖性细胞以细胞因子非依赖性生长。伊马替尼抑制表达 Hes1 和 FIP1L1-PDGFRα 的共同髓系祖细胞的生长，但对具有 T674I 或 D842V 的伊马替尼耐药 FIP1L1-PDGFRα 突变体没有作用。相比之下，ponatinib 有效地消除了体外和体内表达 Hes1 和伊马替尼耐药 FIP1L1-PDGFRΑ 突变体的白血病细胞。因此，我们建立了 FIP1L1-PDGFRA 阳性髓性母细胞急变期白血病的小鼠模型，这将有助于阐明疾病的发病机制并开发新的治疗方法。
