Submitted August 3, 2007
Accepted January 3, 2008
Requirement of c-Myb for p210BCR/ABL-dependent transformation of myeloid progenitors and leukemogenesis
Maria Rosa Lidonnici, Francesca Corradini, Todd Waldron, Timothy P. Bender, and Bruno Calabretta*
Department of Cancer Biology, and Kimmel Cancer Center, Thomas Jefferson University Medical College, Philadelphia, PA, United States
Department of Biomedical Sciences, University of Modena Medical School, Modena, Italy
Department of Microbiology, University of Virginia Health System, Charlottesville, VA, United States
* Corresponding author; email: b_calabretta{at}mail.jci.tju.edu.
The c-Myb gene encodes a transcription factor required for proliferation and survival of normal myeloid progenitors and leukemic blast cells. Targeting of c-Myb by antisense oligodeoxynucleotides has suggested that myeloid leukemia blasts (including CML-blast crisis cells) rely on c-Myb expression more than normal progenitors but a genetic approach to assess the requirement of c-Myb by p210BCR/ABL-transformed myeloid progenitors has not been taken. By comparing different progenitor subsets (Lin-, Lin-Sca-1+, Lin-Sca-1+Kit+) of mice with one or two functional c-Myb alleles, we show here that loss of a c-Myb allele had modest effects (20-25% decrease) on colony formation of non-transduced progenitors while the effect on p210BCR/ABL-expressing progenitors was more pronounced (50-80% decrease). Using a model of CML-blast crisis, mice (n=14) injected with p210BCR/ABL-transduced p53-/-c-Mybw/w marrow cells developed leukemia rapidly and had a median survival of 26 days, while only 67% of mice (n=12) injected with p210BCR/ABL-transduced p53-/-c-Mybw/d marrow cells died of leukemia with a median survival of 96 days. On assessing the expression of c-Myb-regulated genes, p210BCR/ABL-transduced c-Mybw/w and c-Mybw/d marrow progenitors expressed similar levels of c-Myc and cyclin B1 while those of Bcl-2 were reduced. However, ectopic Bcl-2 expression did not enhance colony formation of p210BCR/ABL-transduced c-Mybw/d Lin-Sca-1+Kit+ cells. Together, these studies support the requirement of c-Myb for p210BCR/ABL-dependent leukemogenesis.
