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| Transformation of myeloid progenitors by MLL oncoproteins is dependent on Hoxa7 and Hoxa9 |
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| Author(s): Ayton PM, Cleary ML |
| Source: GENES & DEVELOPMENT Volume: 17 Issue: 18 Pages: 2298-2307 Published: SEP 15 2003 |
| Times Cited: 132 References: 49 |
| Abstract: 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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Cleary, ML (reprint author), Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA |
Addresses:
1. Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA |
| Publisher: COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT, 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA |
| Subject Category: Cell Biology; Developmental Biology; Genetics & Heredity |
| IDS Number: 722NG |
| ISSN: 0890-9369 |
| DOI: 10.1101/gad.1111603 |
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