Integration of Hedgehog and mutant FLT3 signaling in myeloid leukemia.
Integration of Hedgehog and mutant FLT3 signaling in myeloid leukemia.
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DOI：
10.1126/scitranslmed.aaa5731
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发表时间：
2015-06-10
影响因子：
17.1
通讯作者：
Matsui W
中科院分区：
文献类型：
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作者：
Lim Y;Gondek L;Li L;Wang Q;Ma H;Chang E;Huso DL;Foerster S;Marchionni L;McGovern K;Watkins DN;Peacock CD;Levis M;Smith BD;Merchant AA;Small D;Matsui W
导致组成性激酶活性的FLT 3内部串联重复（ITD）突变在急性髓性白血病（AML）中很常见，预后不良。已经开发了几种靶向FLT 3的药物，但其有限的临床活性表明需要抑制导致恶性表型的其他因子。我们检查了基因表达数据集以及原始标本，发现与野生型FLT 3 AML相比，FLT 3-ITD中Hedgehog（Hh）信号通路的主要效应子GLI 2的表达增加。为了检查Hh通路的功能作用，我们研究了Flt 3-ITD表达导致惰性骨髓增殖状态的小鼠，发现组成性Hh信号传导通过增强STAT 5信号传导和骨髓髓系祖细胞的增殖加速AML的发展。此外，FLT 3和Hh通路的联合抑制在体外和体内限制了白血病的生长，这种方法可以作为FLT 3-ITD AML的治疗策略。
FLT3 internal tandem duplication (ITD) mutations resulting in constitutive kinase activity are common in acute myeloid leukemia (AML) and carry a poor prognosis. Several agents targeting FLT3 have been developed, but their limited clinical activity suggests that the inhibition of other factors contributing to the malignant phenotype is required. We examined gene expression data sets as well as primary specimens and found that the expression of GLI2, a major effector of the Hedgehog (Hh) signaling pathway, was increased in FLT3-ITD compared to wild type FLT3 AML. To examine the functional role of the Hh pathway, we studied mice in which Flt3-ITD expression results in an indolent myeloproliferative state and found that constitutive Hh signaling accelerated the development of AML by enhancing STAT5 signaling and the proliferation of bone marrow myeloid progenitors. Furthermore, combined FLT3 and Hh pathway inhibition limited leukemic growth in vitro and in vivo, and this approach may serve as a therapeutic strategy for FLT3-ITD AML.