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

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.