title: Requirement of c-Myb for p210(BCR/ABL)-dependent transformation of hematopoietic progenitors and leukemogenesis.
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 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.
authors.affiliation: Department of Cancer Biology, and Kimmel Cancer Center, Thomas Jefferson University Medical College, Philadelphia, PA 19107, USA.
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Lidonnici
authors.forename: Francesca
authors.initials: F
authors.lastname: Corradini
authors.forename: Todd
authors.initials: T
authors.lastname: Waldron
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Bender
authors.forename: Bruno
authors.initials: B
authors.lastname: Calabretta
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D016044:Fusion Proteins, bcr-abl / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D007938:Leukemia / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental; D020598:Proto-Oncogene Proteins c-myb / Q000502:physiology*; D014161:Transduction, Genetic
chemical_list: D020598:Proto-Oncogene Proteins c-myb; D016044:Fusion Proteins, bcr-abl