Fyn is not essential for Bcr-Abl-induced leukemogenesis in mouse bone marrow transplantation models
Fyn is not essential for Bcr-Abl-induced leukemogenesis in mouse bone marrow transplantation models
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DOI：
10.1007/s12185-011-0994-5
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发表时间：
2012-02-01
影响因子：
2.1
通讯作者：
Kitamura, Toshio
中科院分区：
文献类型：
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作者：
Doki, Noriko;Kitaura, Jiro;Kitamura, Toshio
Bcr-Abl癌基因可引起人费城染色体阳性（Ph+）白血病，包括b细胞急性淋巴细胞白血病（B-ALL）和慢性髓性白血病（CML）伴慢性期（CML- cp）至细胞危象（CML- bc）。先前的研究表明，Src家族激酶是诱导B-ALL所必需的，但不是由小鼠Bcr-Abl诱导的CML。相比之下，有报道称，与CML-CP相比，Fyn在人CML-BC中表达上调，暗示Fyn参与了细胞危机的转变。在这里，我们旨在描述Fyn在Ph+白血病诱导/进展中的确切作用。我们发现Fyn在不同发育阶段的小鼠造血细胞中表达，包括c-kit(+)Sca-1(+)Lin（-）细胞。值得注意的是，Fyn在一些人类淋巴瘤中高表达，但在人类Ph+白血病（包括CML-BC）中不表达。在小鼠骨髓移植模型中，移植了Bcr-Abl转导的野生型或fynn缺陷骨髓细胞的小鼠在B-ALL或cml样疾病的发展方面没有差异。同样，Fyn缺乏也不能影响Bcr-Abl和Hes1诱导的髓性CML-BC的发展。在bcr - abl介导的CML和CML- bc样疾病的小鼠样本中未发现Fyn表达升高。因此，bcr - abl介导的白血病的发病机制不需要Fyn。
The Bcr-Abl oncogene causes human Philadelphia chromosome-positive (Ph+) leukemias, including B-cell acute lymphoblastic leukemia (B-ALL) and chronic myeloid leukemia (CML) with chronic phase (CML-CP) to blast crisis (CML-BC). Previous studies have demonstrated that Src family kinases are required for the induction of B-ALL, but not for CML, which is induced by Bcr-Abl in mice. In contrast, it has been reported that Fyn is up-regulated in human CML-BC compared with CML-CP, implicating Fyn in the blast crisis transition. Here, we aimed to delineate the exact role of Fyn in the induction/progression of Ph+ leukemias. We found that Fyn is expressed in mouse hematopoietic cells at varying stages of development, including c-kit(+)Sca-1(+)Lin(-) cells. Notably, Fyn is highly expressed in some of human lymphomas, but not in human Ph+ leukemias including CML-BC. In mouse bone marrow transplantation models, mice transplanted with wild-type or Fyn-deficient bone marrow cells transduced with Bcr-Abl showed no differences in the development of B-ALL or CML-like diseases. Similarly, Fyn deficiency failed to impact the development of myeloid CML-BC induced by Bcr-Abl and Hes1. Elevated expression of Fyn was not found in mouse samples of Bcr-Abl-mediated CML- and CML-BC-like diseases. Thus, Fyn is not required for the pathogenesis of Bcr-Abl-mediated leukemias.