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 Blood, 1 July 2006, Vol. 108, No. 1, pp. 297-304.
Prepublished online as a Blood First Edition Paper on February 28, 2006; DOI 10.1182/blood-2005-12-5014.

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NEOPLASIA

c-Myb is an essential downstream target for homeobox-mediated transformation of hematopoietic cells

Jay L. Hess, Claudia B. Bittner, Deniz T. Zeisig, Christian Bach, Uta Fuchs, Arndt Borkhardt, Jon Frampton, and Robert K. Slany

From the Department of Pathology, University of Michigan Medical School, Ann Arbor, MI; Department of Genetics, University Erlangen, Germany; Department of Pediatric Hematology & Oncology, Dr von Hauner Children's Hospital, Munich, Germany; and Division of Immunity and Infection, Birmingham University Medical School, Birmingham, United Kingdom.

Abdominal-type HoxA genes in combination with Meis1 are well-documented on-cogenes in various leukemias but it is unclear how they exert their transforming function. Here we used a system of conditional transformation by an inducible mixed lineage leukemia-eleven-nineteen leukemia (MLL-ENL) oncoprotein to overexpress Hoxa9 and Meis1 in primary hematopoietic cells. Arrays identified c-Myb and a c-Myb target (Gstm1) among the genes with the strongest response to Hoxa9/Meis1. c-Myb overexpression was verified by Northern blot and quantitative reverse transcription-polymerase chain reaction (RT-PCR). Also MLL-ENL activated c-Myb through up-regulation of Hoxa9 and Meis1. Consequently, short-term suppression of c-Myb by small inhibitory RNA (siRNA) efficiently inhibited transformation by MLL-ENL but did not impair transformation by transcription factor E2A-hepatic leukemia factor (E2A-HLF). The anti c-Myb siRNA effect was abrogated by coexpression of a c-Myb derivative with a mutated siRNA target site. The introduction of a dominant-negative c-Myb mutant had a similar but weaker effect on MLL-ENL-mediated transformation. Hematopoietic precursors from mice homozygous for a hypo-morphic c-Myb allele were more severely affected and could be transformed neither by MLL-ENL nor by E2A-HLF. Ectopic expression of c-Myb induced a differentiation block but c-Myb alone was not transforming in a replating assay similar to Hoxa9/Meis1. These results suggest that c-Myb is essential but not sufficient for Hoxa9/Meis1 mediated transformation. (Blood. 2006;108:297-304)


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