Acquired expression of CblQ367P in mice induces dysplastic myelopoiesis mimicking chronic myelomonocytic leukemia
Acquired expression of CblQ367P in mice induces dysplastic myelopoiesis mimicking chronic myelomonocytic leukemia
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CblQ367P在小鼠中的获得性表达诱导类似慢性粒单核细胞白血病的发育不良骨髓生成
DOI：
10.1182/blood-2016-06-724658
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发表时间：
2017-04-13
期刊：
影响因子：
20.3
通讯作者：
Honda, Hiroaki
中科院分区：
文献类型：
--
作者：
Nakata, Yuichiro;Ueda, Takeshi;Honda, Hiroaki
慢性粒单核细胞白血病(CMML)是一种以骨髓单核细胞增殖异常为特征的血液系统恶性肿瘤，常进展为急性髓系白血病(AML)。我们在部分CMML患者中发现了Cbl基因的突变，Cbl基因编码细胞因子信号的负调节因子。为了研究突变Cbl在CMML发病机制中的作用，我们建立了稳定表达野生型Cbl并诱导表达CMML相关Cbl突变体Cbl(Q367P)的Cbl条件性敲打小鼠。CBL(Q367P)小鼠表现为骨髓单核细胞持续增殖、多系发育不良和脾肿大，这些都是CMML的特征。在Cbl(Q367P)造血干细胞中，磷脂酰肌醇3-激酶(PI3K)-AKT和JAK-STAT信号通路被结构性激活，促进细胞周期进程，增强趋化因子-趋化因子受体活性。GEM是一种编码GTP酶的基因，由Cbl(Q367P)上调，能增强造血干细胞的活性，并诱导髓系细胞增殖。此外，转录因子基因Evi1与Cb1(Q367P)协同作用，将CMML进展为AML。此外，靶向抑制PI3K-AKT和JAK-STAT通路可有效抑制携带Cbl(Q367P)的CMML细胞的增殖活性。我们的发现提供了对突变Cbl诱导CMML的分子机制的见解，并提出了一种可能的分子靶向治疗突变Cbl携带者的CMML患者。
Chronic myelomonocytic leukemia (CMML) is a hematological malignancy characterized by uncontrolled proliferation of dysplastic myelomonocytes and frequent progression to acute myeloid leukemia (AML). We identified mutations in the Cbl gene, which encodes a negative regulator of cytokine signaling, in a subset of CMML patients. To investigate the contribution of mutant Cbl in CMML pathogenesis, we generated conditional knockin mice for Cbl that express wild-type Cbl in a steady state and inducibly express Cbl(Q367P), a CMML-associated Cbl mutant. Cbl(Q367P) mice exhibited sustained proliferation of myelomonocytes, multilineage dysplasia, and splenomegaly, which are the hallmarks of CMML. The phosphatidylinositol 3-kinase (PI3K)-AKT and JAK-STAT pathways were constitutively activated in Cbl(Q367P) hematopoietic stem cells, which promoted cell cycle progression and enhanced chemokine-chemokine receptor activity. Gem, a gene encoding a GTPase that is upregulated by Cbl(Q367P), enhanced hematopoietic stem cell activity and induced myeloid cell proliferation. In addition, Evi1, a gene encoding a transcription factor, was found to cooperate with Cbl(Q367P) and progress CMML to AML. Furthermore, targeted inhibition for the PI3K-AKT and JAK-STAT pathways efficiently suppressed the proliferative activity of Cbl(Q367P) -bearing CMML cells. Our findings provide insights into the molecular mechanisms underlying mutant Cbl-induced CMML and propose a possible molecular targeting therapy for mutant Cbl-carrying CMML patients.