The role of HOXB2 and HOXB3 in acute myeloid leukemia
The role of HOXB2 and HOXB3 in acute myeloid leukemia
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DOI：
10.1016/j.bbrc.2015.10.071
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发表时间：
2015-11-27
影响因子：
3.1
通讯作者：
Ronnstrand, Lars
中科院分区：
文献类型：
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作者：
Lindblad, Oscar;Chougule, Rohit A.;Ronnstrand, Lars
急性髓性白血病（AML）是一种异质性侵袭性疾病，也是成人白血病中最常见的形式。在超过30%的AML患者中发现了III型受体酪氨酸激酶FLT 3的突变。针对FLT 3的药物已被开发用于治疗AML，但它们缺乏特异性，反应差，并导致治疗后产生耐药表型。因此，对FLT 3信号传导的更深入理解将有助于在FLT 3驱动的AML中识别其他药理学靶点。在这份报告中，我们确定HOXB 2和HOXB 3作为致癌FLT 3-ITD驱动的AML的新调节因子。我们表明，HOXB 2和HOXB 3表达在一组携带FLT 3-ITD的AML患者中上调。HOXB 2或HOXB 3在小鼠pro-B细胞中的过表达导致FLT 3-ITD依赖性细胞增殖以及集落形成减少和凋亡增加。HOXB 2或HOXB 3的表达导致FLT 3-ITD诱导的AKT、ERR、p38和STAT 5磷酸化显著降低。我们的数据表明HOXB 2和HOXB 3在FLT 3-ITD驱动的AML中充当肿瘤抑制剂。(C)2015 Elsevier Inc. All rights reserved.
Acute myeloid leukemia (AML) is a heterogeneous aggressive disease and the most common form of adult leukemia. Mutations in the type III receptor tyrosine kinase FLT3 are found in more than 30% of AML patients. Drugs against FLT3 have been developed for the treatment of AML, but they lack specificity, show poor response and lead to the development of a resistant phenotype upon treatment. Therefore, a deeper understanding of FLT3 signaling will facilitate identification of additional pharmacological targets in FLT3-driven AML. In this report, we identify HOXB2 and HOXB3 as novel regulators of oncogenic FLT3-ITD-driven AML We show that HOXB2 and HOXB3 expression is upregulated in a group of AML patients carrying FLT3-ITD. Overexpression of HOXB2 or HOXB3 in mouse pro-B cells resulted in decreased FLT3-ITD-dependent cell proliferation as well as colony formation and increased apoptosis. Expression of HOXB2 or HOXB3 resulted in a significant decrease in FLT3-ITD-induced AKT, ERR, p38 and STAT5 phosphorylation. Our data suggest that HOXB2 and HOXB3 act as tumor suppressors in FLT3-ITD driven AML. (C) 2015 Elsevier Inc. All rights reserved.