HOXA9 is required for survival in human MLL-rearranged acute leukemias
HOXA9 is required for survival in human MLL-rearranged acute leukemias
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DOI：
10.1182/blood-2007-09-113597
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发表时间：
2009-03-12
期刊：
影响因子：
20.3
通讯作者：
Armstrong, Scott A.
中科院分区：
文献类型：
--
作者：
Faber, Joerg;Krivtsov, Andrei V.;Armstrong, Scott A.
混合系白血病基因（MLL）易位的白血病具有独特的生物学特征，通常预后不良。基因表达分析表明，MLL重排白血病具有不同的特征，选择的同源框基因（包括HOXA 9）表达水平一致。在这里，我们研究了HOXA 9抑制的影响，在MLL重排和MLL生殖系白血病使用RNA干扰。HOXA 9抑制后的基因表达谱分析表明，在人MLL-AML和鼠MLL-白血病干细胞中高度表达的程序（包括HOXA 10、MEIS 1、PBX 3和MEF 2C）共下调。我们证明，在17个人AML/ALL细胞系（7个ML重排，10个ML生殖细胞系）中HOXA 9缺失诱导增殖停滞和细胞凋亡，特别是在ML重排细胞中（P = .007）。类似地，原发性AML的评估表明，HOXA 9抑制在ML重排样品中更大程度地诱导细胞凋亡（P = .01）。此外，移植HOXA 9缺失t（4; 11）SEMK 2细胞的小鼠显示白血病负荷显著降低，因此确定了HOXA 9在体内白血病存活中的作用。我们的数据表明HOXA 9在人类MLL重排白血病中的重要作用，并表明靶向HOXA 9或下游程序可能是一种新的治疗选择。（血。2009; 113：2375-2385）
Leukemias that harbor translocations involving the mixed lineage leukemia gene (MLL) possess unique biologic characteristics and often have an unfavorable prognosis. Gene expression analyses demonstrate a distinct profile for MLL-rearranged leukemias with consistent high-level expression of select Homeobox genes, including HOXA9. Here, we investigated the effects of HOXA9 suppression in MLL-rearranged and MLL-germline leukemias using RNA interference. Gene expression profiling after HOXA9 suppression demonstrated co-down-regulation of a program highly expressed in human MLL-AML and murine MLL-leukemia stem cells, including HOXA10, MEIS1, PBX3, and MEF2C. We demonstrate that HOXA9 depletion in 17 human AML/ALL cell lines ( 7 MLL-rearranged, 10 MLL-germline) induces proliferation arrest and apoptosis specifically in MLL-rearranged cells ( P = .007). Similarly, assessment of primary AMLs demonstrated that HOXA9 suppression induces apoptosis to a greater extent in MLL-rearranged samples ( P = .01). Moreover, mice transplanted with HOXA9-depleted t(4; 11) SEMK2 cells revealed a significantly lower leukemia burden, thus identifying a role for HOXA9 in leukemia survival in vivo. Our data indicate an important role for HOXA9 in human MLL-rearranged leukemias and suggest that targeting HOXA9 or downstream programs may be a novel therapeutic option. ( Blood. 2009; 113: 2375-2385)