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c-Myb is an essential downstream target for homeobox-mediated transformation of hematopoietic cells
- Source :
- Blood. 108(1)
- Publication Year :
- 2006
-
Abstract
- 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)
- Subjects :
- animal structures
Immunology
Biology
Biochemistry
Mice
Proto-Oncogene Proteins c-myb
hemic and lymphatic diseases
medicine
Animals
MYB
Northern blot
Myeloid Ecotropic Viral Integration Site 1 Protein
Transcription factor
Glutathione Transferase
Homeodomain Proteins
Leukemia
Neoplasia
Gene Expression Regulation, Leukemic
Reverse Transcriptase Polymerase Chain Reaction
Gene Expression Profiling
Hematopoietic Stem Cell Transplantation
RNA
Cell Biology
Hematology
medicine.disease
Blotting, Northern
Hematopoietic Stem Cells
Molecular biology
Neoplasm Proteins
Up-Regulation
Transformation (genetics)
Cell Transformation, Neoplastic
Ectopic expression
Subjects
Details
- ISSN :
- 00064971
- Volume :
- 108
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....724410925d7f0f16b38c07c7c20e7a0d