Expression of p89 c-Mybex9b, an alternatively spliced form of c-Myb, is required for proliferation and survival of p210BCR/ABL-expressing cells

The c-Myb gene encodes the p75 ^c-Myb isoform and less-abundant proteins generated by alternatively spliced transcripts. Among these, the best known is p89 ^c-Mybex9b, which contains 121 additional amino acids between exon 9 and 10, in a domain involved in protein-protein interactions and negative regulation. In hematopoietic cells, expression of p89 ^c-Mybex9b accounts for 10-15% of total c-Myb; these levels may be biologically relevant because modest changes in c-Myb expression affects proliferation and survival of leukemic cells and lineage choice and frequency of normal hematopoietic progenitors. In this study, we assessed biochemical activities of p89 ^c-Mybex9b and the consequences of perturbing its expression in K562 and primary chronic myeloid leukemia (CML) progenitor cells. Compared with p75 ^c-Myb, p89 ^c-Mybex9b is more stable and more effective in transactivating Myb-regulated promoters. Ectopic expression of p89 ^c-Mybex9b enhanced proliferation and colony formation and reduced imatinib (IM) sensitivity of K562 cells; conversely, specific downregulation of p89 ^c-Mybex9b reduced proliferation and colony formation, enhanced IM sensitivity of K562 cells and markedly suppressed colony formation of CML CD34 ⁺ cells, without affecting the levels of p75 ^c-Myb. Together, these studies indicate that expression of the low-abundance p89 ^c-Mybex9b isoform has an important role for the overall biological effects of c-Myb in BCR/ABL-transformed cells.