title: c-Myb and its target Bmi1 are required for p190BCR/ABL leukemogenesis in mouse and human cells.
abstract: Expression of c-Myb is required for normal hematopoiesis and for proliferation of myeloid leukemia blasts and a subset of T-cell leukemia, but its role in B-cell leukemogenesis is unknown. We tested the role of c-Myb in p190(BCR/ABL)-dependent B-cell leukemia in mice transplanted with p190(BCR/ABL)-transduced marrow cells with a c-Myb allele (Myb(f/d)) and in double transgenic p190(BCR/ABL)/Myb(w/d) mice. In both models, loss of a c-Myb allele caused a less aggressive B-cell leukemia. In p190(BCR/ABL)-expressing human B-cell leukemia lines, knockdown of c-Myb expression suppressed proliferation and colony formation. Compared with c-Myb(w/f) cells, expression of Bmi1, a regulator of stem cell proliferation and maintenance, was decreased in pre-B cells from Myb(w/d) p190(BCR/ABL) transgenic mice. Ectopic expression of a mutant c-Myb or Bmi1 enhanced the proliferation and colony formation of Myb(w/d) p190(BCR/ABL) B-cells; by contrast, Bmi1 downregulation inhibited colony formation of p190(BCR/ABL)-expressing murine B cells and human B-cell leukemia lines. Moreover, c-Myb interacted with a segment of the human Bmi1 promoter and enhanced its activity. In blasts from 19 Ph(1) adult acute lymphoblastic leukemia patients, levels of c-Myb and Bmi1 showed a positive correlation. Together, these findings support the existence of a c-Myb-Bmi1 transcription-regulatory pathway required for p190(BCR/ABL) leukemogenesis.
authors.affiliation: Department of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: T
authors.initials: T
authors.lastname: Waldron
authors.forename: M
authors.initials: M
authors.lastname: De Dominici
authors.forename: A R
authors.initials: AR
authors.lastname: Soliera
authors.forename: A
authors.initials: A
authors.lastname: Audia
authors.forename: I
authors.initials: I
authors.lastname: Iacobucci
authors.forename: A
authors.initials: A
authors.lastname: Lonetti
authors.forename: G
authors.initials: G
authors.lastname: Martinelli
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: R
authors.initials: R
authors.lastname: Martinez
authors.forename: T
authors.initials: T
authors.lastname: Hyslop
authors.forename: T P
authors.initials: TP
authors.lastname: Bender
authors.forename: B
authors.initials: B
authors.lastname: Calabretta
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D006801:Humans; D015448:Leukemia, B-Cell / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D048054:Mitogen-Activated Protein Kinase 7 / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D020598:Proto-Oncogene Proteins c-myb / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*
chemical_list: C489421:Bmi1 protein, mouse; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1; D016044:Fusion Proteins, bcr-abl; C481581:MAPK7 protein, human; D048054:Mitogen-Activated Protein Kinase 7