Requirement of c-Myb for p210BCR/ABL-dependent transformation of hematopoietic progenitors and leukemogenesis

MR Lidonnici, F Corradini, T Waldron… - Blood, The Journal …, 2008 - ashpublications.org
MR Lidonnici, F Corradini, T Waldron, TP Bender, B Calabretta
Blood, The Journal of the American Society of Hematology, 2008ashpublications.org
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 chronic
myelogenous leukemia [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 hematopoietic progenitors has not been taken. We show here that loss of a c …
Abstract
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 chronic myelogenous leukemia [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 hematopoietic progenitors has not been taken. We show here that loss of a c-Myb allele had modest effects (20%-28% decrease) on colony formation of nontransduced progenitors, while the effect on p210BCR/ABL-expressing Lin Sca-1+ and Lin Sca-1+Kit+ cells 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. p210BCR/ABL-transduced c-Mybw/w and c-Mybw/d marrow progenitors expressed similar levels of the c-Myb–regulated genes 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 LinSca-1+Kit+ cells. Together, these studies support the requirement of c-Myb for p210BCR/ABL-dependent leukemogenesis.
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