title: Expression of p89(c-Mybex9b), an alternatively spliced form of c-Myb, is required for proliferation and survival of p210BCR/ABL-expressing cells.
abstract: 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 p(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 p(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 p(c-Mybex9b) and the consequences of perturbing its expression in K562 and primary chronic myeloid leukemia (CML) progenitor cells. Compared with p75(c-Myb), p(c-Mybex9b) is more stable and more effective in transactivating Myb-regulated promoters. Ectopic expression of p(c-Mybex9b) enhanced proliferation and colony formation and reduced imatinib (IM) sensitivity of K562 cells; conversely, specific downregulation of p(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 p(c-Mybex9b) isoform has an important role for the overall biological effects of c-Myb in BCR/ABL-transformed cells.
authors: G
authors: G
authors: Manzotti
authors: S A
authors: SA
authors: Mariani
authors: F
authors: F
authors: Corradini
authors: R
authors: R
authors: Bussolari
authors: V
authors: V
authors: Cesi
authors: J
authors: J
authors: Vergalli
authors: G
authors: G
authors: Ferrari-Amorotti
authors: V
authors: V
authors: Fragliasso
authors: A R
authors: AR
authors: Soliera
authors: S
authors: S
authors: Cattelani
authors: G
authors: G
authors: Raschellà
authors: T L
authors: TL
authors: Holyoake
authors: B
authors: B
authors: Calabretta