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

摘要

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 p210^BCR/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 p210^BCR/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 p210^BCR/ABL-transduced p53^−/−c-Myb^w/w marrow cells developed leukemia rapidly and had a median survival of 26 days, while only 67% of mice (n = 12) injected with p210^BCR/ABL-transduced p53^−/−c-Myb^w/d marrow cells died of leukemia with a median survival of 96 days. p210^BCR/ABL-transduced c-Myb^w/w and c-Myb^w/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 p210^BCR/ABL-transduced c-Myb^w/d Lin⁻Sca-1⁺Kit⁺ cells. Together, these studies support the requirement of c-Myb for p210^BCR/ABL-dependent leukemogenesis.