Genetic and pharmacologic evidence implicating the p85α, but not p85β, regulatory subunit of PI3K and Rac2 GTPase in regulating oncogenic KIT-induced transformation in acute myeloid leukemia and systemic mastocytosis
Genetic and pharmacologic evidence implicating the p85α, but not p85β, regulatory subunit of PI3K and Rac2 GTPase in regulating oncogenic KIT-induced transformation in acute myeloid leukemia and systemic mastocytosis
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DOI：
10.1182/blood-2006-10-053058
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发表时间：
2007-09-01
期刊：
影响因子：
20.3
通讯作者：
Kapur, Reuben
中科院分区：
文献类型：
--
作者：
Munugalavadla, Veerendra;Sims, Emily C.;Kapur, Reuben
在急性髓性白血病（AML）和系统性肥大细胞增多症（SM）中观察到致癌激活环KIT突变；然而，与KIT近膜突变体不同，激活环突变体对甲磺酸伊马替尼不敏感。此外，由于先前的研究主要使用异种细胞系，因此对kit诱导原代细胞中致癌转化的分子机制知之甚少。研究表明，KITD814V在原代造血干细胞/祖细胞（HSC/Ps）和肥大细胞祖细胞（MCps）中的表达可诱导组成性KIT自磷酸化，支持不依赖配体的过度增殖，并促进与多种细胞因子的混杂合作。p85 α的遗传破坏。研究表明，IA类脂质激酶磷酸肌醇3激酶（PI3K）的调控亚基，但不包括p85 β，或造血细胞特异性Rho GTPase （Rac2）的遗传破坏，使kitd814v诱导的不依赖配体的过度增殖正常化。此外，在表达kitd814v的HSC/Ps和MCps中，缺乏p85a或Rac2纠正了对多种细胞因子的反应中观察到的混杂过度增殖。用Rac抑制剂（NC23766）或雷帕霉素治疗表达kitd814v的HSC/Ps显示出对配体非依赖性生长的剂量依赖性抑制。综上所述，我们的研究结果确定p85a和Rac2是治疗kitd814v携带的AML和SM的潜在新治疗靶点。
Oncogenic activation loop KIT mutations are observed in acute myeloid leukemia (AML) and systemic mastocytosis (SM); however, unlike the KIT juxtamembrane mutants, the activation loop mutants are insensitive to imatinib mesylate. Furthermore, as prior studies primarily used heterologous cell lines, the molecular mechanism(s) underlying oncogenic KIT-induced transformation in primary cells is poorly understood. We demonstrate that expression of KITD814V in primary hema-topoietic stem/progenitor cells (HSC/Ps) and mast cell progenitors (MCps) induces constitutive KIT autophosphorylation, supports ligand-independent hyperproliferation, and promotes promiscuous cooperation with multiple cytokines. Genetic disruption of p85 alpha., the regulatory subunit of class IA lipid kinase phosphoinositol-3kinase (PI3K), but not of p85 beta, or genetic disruption of the hematopoietic cell-specific Rho GTPase, Rac2, normalizes KITD814V-Induced ligand-independent hyperproliferation. Additionally, deficiency of p85a or Rac2 corrects the promiscuous hyperproliferation observed in response to multiple cytokines in both KITD814V-expressing HSC/Ps and MCps. Treatment of KITD814V-expressing HSC/Ps with a Rac inhibitor (NC23766) or with rapamycin showed a dose-dependent suppression in ligand-independent growth. Taken together, our results identify p85a and Rac2 as potential novel therapeutic targets for the treatment of KITD814V-bearing AML and SM.