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 p190BCR/ABL-dependent B-cell leukemia in mice transplanted with p190BCR/ABL-transduced marrow cells with a c-Myb allele (Mybf/d) and in double transgenic p190BCR/ABL/Mybw/d mice. In both models, loss of a c-Myb allele caused a less aggressive B-cell leukemia.In p190BCR/ABL expressing human B-cell leukemia lines, knockdown of c-Myb expression suppressed proliferation and colony formation.Compared to c-Mybw/f cells, expression of Bmi1, a regulator of stem cell proliferation and maintenance, was decreased in pre-B cells from Mybw/d p190BCR/ABL transgenic mice. Ectopic expression of a mutant c-Myb or Bmi1 enhanced the proliferation and colony formation of Mybw/d p190BCR/ABL B-cells; by contrast, Bmi1 downregulation inhibited colony formation of p190BCR/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 nineteen Ph1 adult ALL 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 p190BCR/ABL leukemogenesis.