NrasG12D oncoprotein inhibits apoptosis of preleukemic cells expressing Cbfβ-SMMHC via activation of MEK/ERK axis
NrasG12D oncoprotein inhibits apoptosis of preleukemic cells expressing Cbfβ-SMMHC via activation of MEK/ERK axis
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DOI：
10.1182/blood-2013-12-541730
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发表时间：
2014-07-17
期刊：
影响因子：
20.3
通讯作者：
Castilla, Lucio H.
中科院分区：
文献类型：
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作者：
Xue, Liting;Pulikkan, John A.;Castilla, Lucio H.
急性髓性白血病（AML）是由驱动突变的活性引起的，该驱动突变使造血干细胞（HSC）的增殖和存活失调。融合蛋白CBF β-SMMHC损害造血干细胞和祖细胞的分化，并与其他突变协同诱导AML。然而，CBF β-SMMHC和协同突变在白血病前期扩展中的组合功能尚不清楚。在这里，我们使用Nras（LSL-G12 D）; Cbfb（56 M）敲入小鼠来显示致癌Nras（G12 D）和Cbf β-SMMHC的等位基因表达增加了白血病前期短期HSC和骨髓祖细胞的存活，并维持了融合蛋白诱导的分化阻断。Nras（G12 D）和Cbf β-SMMHC协同作用以细胞毒性方式诱导小鼠白血病，与表达Cbf β-SMMHC的小鼠相比，具有更短的中位潜伏期和更高的白血病起始细胞活性。此外，Nras（LSL-G12 D）; Cbfb（56 M）白血病细胞对MEK/ERK信号通路的药物抑制敏感，增加了细胞凋亡和Bim蛋白水平。这些研究表明，Cbf β-SMMHC和Nras（G12 D）通过激活MEK/ERK/Bim轴促进白血病前期髓系祖细胞的存活，并将Nras（LSL-G12 D）; Cbfb（56 M）小鼠定义为研究倒位（16）AML靶向治疗的有价值的遗传模型。
Acute myeloid leukemia (AML) results from the activity of driver mutations that deregulate proliferation and survival of hematopoietic stem cells (HSCs). The fusion protein CBF beta-SMMHC impairs differentiation in hematopoietic stem and progenitor cells and induces AML in cooperation with other mutations. However, the combined function of CBF beta-SMMHC and cooperating mutations in preleukemic expansion is not known. Here, we used Nras(LSL-G12D); Cbfb(56M) knock-in mice to show that allelic expression of oncogenic Nras(G12D) and Cbf beta-SMMHC increases survival of preleukemic short-term HSCs and myeloid progenitor cells and maintains the differentiation block induced by the fusion protein. Nras(G12D) and Cbf beta-SMMHC synergize to induce leukemia in mice in a cellautonomous manner, with a shorter median latency and higher leukemia-initiating cell activity than that of mice expressing Cbf beta-SMMHC. Furthermore, Nras(LSL-G12D); Cbfb(56M) leukemic cells were sensitive to pharmacologic inhibition of the MEK/ERK signaling pathway, increasing apoptosis and Bim protein levels. These studies demonstrate that Cbf beta-SMMHC and Nras(G12D) promote the survival of preleukemic myeloid progenitors primed for leukemia by activation of the MEK/ERK/Bim axis, and define Nras(LSL-G12D); Cbfb(56M) mice as a valuable genetic model for the study of inversion(16) AML-targeted therapies.