c-Myb and its target Bmi1 are required for p190BCR/ABL leukemogenesis in mouse and human cells

Leukemia. 2012 Apr;26(4):644-53. doi: 10.1038/leu.2011.264. Epub 2011 Sep 30.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Cell Transformation, Neoplastic* / pathology
  • Fusion Proteins, bcr-abl / physiology*
  • Humans
  • Leukemia, B-Cell / etiology*
  • Leukemia, B-Cell / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase 7 / physiology*
  • Nuclear Proteins / physiology*
  • Polycomb Repressive Complex 1
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-myb / physiology*
  • Repressor Proteins / physiology*

Substances

  • Bmi1 protein, mouse
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-myb
  • Repressor Proteins
  • Polycomb Repressive Complex 1
  • Fusion Proteins, bcr-abl
  • MAPK7 protein, human
  • Mitogen-Activated Protein Kinase 7