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

摘要

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 to 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 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 p190^BCR/ABL leukemogenesis.