Transformation of myeloid progenitors by MLL oncoproteins is dependent on Hoxa7 and Hoxa9
Transformation of myeloid progenitors by MLL oncoproteins is dependent on Hoxa7 and Hoxa9
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DOI：
10.1101/gad.1111603
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发表时间：
2003-09-15
影响因子：
10.5
通讯作者：
Cleary, ML
中科院分区：
文献类型：
--
作者：
Ayton, PM;Cleary, ML
通过产生源自染色体易位的显性作用嵌合转录因子而导致的转录失调是急性白血病发病机制中的一个常见主题。然而，急性白血病发生的重要靶基因尚不清楚。我们在此证明，由各种 MLL 癌蛋白永生化的原代骨髓祖细胞表现出特征性的 Hoxa 基因簇表达谱，这反映了该基因簇优先在正常骨髓的骨髓克隆祖细胞部分中表达。这种 MLL 依赖性 Hoxa 基因表达谱的持续维持与条件性 MLL 相关骨髓永生化有关。此外，Hoxa7 和 Hoxa9 是 MLL 融合蛋白（而非其他致白血病融合蛋白）有效体外骨髓永生化所特别需要的。最后，在骨髓转导/移植模型中，Hoxa9 对于体内 MLL 依赖性白血病发生至关重要，这是在疾病发生的最早阶段检测到的主要要求。因此，MLL介导的转化中对Hoxa7和Hoxa9的遗传依赖证明了MLL癌蛋白作为上游组成型激活剂通过Hox依赖性机制促进骨髓转化的功能获得机制。
Transcriptional deregulation through the production of dominant-acting chimeric transcription factors derived from chromosomal translocations is a common theme in the pathogenesis of acute leukemias; however, the essential target genes for acute leukemogenesis are unknown. We demonstrate here that primary myeloid progenitors immortalized by various MLL oncoproteins exhibit a characteristic Hoxa gene cluster expression profile, which reflects that preferentially expressed in the myeloid clonogenic progenitor fraction of normal bone marrow. Continued maintenance of this MLL-dependent Hoxa gene expression profile is associated with conditional MLL-associated myeloid immortalization. Moreover, Hoxa7 and Hoxa9 were specifically required for efficient in vitro myeloid immortalization by an MLL fusion protein but not other leukemogenic fusion proteins. Finally, in a bone marrow transduction/transplantation model, Hoxa9 is essential for MLL-dependent leukemogenesis in vivo, a primary requirement detected at the earliest stages of disease initiation. Thus, a genetic reliance on Hoxa7 and Hoxa9 in MLL-mediated transformation demonstrates a gain-of-function mechanism for MLL oncoproteins as upstream constitutive activators that promote myeloid transformation via a Hox-dependent mechanism.