Ayton Paul M, Cleary Michael L
Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.
Genes Dev. 2003 Sep 15;17(18):2298-307. doi: 10.1101/gad.1111603. Epub 2003 Sep 2.
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.
通过产生源自染色体易位的显性作用嵌合转录因子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，急性白血病发生的关键靶基因尚不清楚。我们在此证明，由各种MLL癌蛋白永生化的原代髓系祖细胞表现出特征性的Hoxa基因簇表达谱，这反映了在正常骨髓的髓系克隆祖细胞部分中优先表达的情况。这种依赖MLL的Hoxa基因表达谱的持续维持与条件性MLL相关的髓系永生化有关。此外，Hoxa7和Hoxa9是MLL融合蛋白高效体外髓系永生化所特需的，但其他致白血病融合蛋白则不需要。最后，在骨髓转导/移植模型中，Hoxa9对于体内MLL依赖的白血病发生至关重要，这是在疾病起始的最早阶段检测到的一个主要需求。因此，在MLL介导的转化中对Hoxa7和Hoxa9的遗传依赖性证明了MLL癌蛋白作为上游组成型激活剂的功能获得机制，其通过Hox依赖机制促进髓系转化。
