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, Robert K. Slany

Research output: Contribution to journalArticle

116 Scopus citations

Abstract

Abdominal-type HoxA genes in combination with Meis1 are well-documented oncogenes 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, shortterm 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 hypomorphic 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.

Original languageEnglish (US)
Pages (from-to)297-304
Number of pages8
JournalBlood
Volume108
Issue number1
DOIs
StatePublished - Jul 1 2006
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Hess, J. L., Bittner, C. B., Zeisig, D. T., Bach, C., Fuchs, U., Borkhardt, A., Frampton, J., & Slany, R. K. (2006). c-Myb is an essential downstream target for homeobox-mediated transformation of hematopoietic cells. Blood, 108(1), 297-304. https://doi.org/10.1182/blood-2005-12-5014