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

G. Manzotti, S. A. Mariani, F. Corradini, R. Bussolari, V. Cesi, J. Vergalli, G. Ferrari-Amorotti, V. Fragliasso, A. R. Soliera, S. Cattelani, G. Raschellà, T. L. Holyoake, B. Calabretta

Research output: Contribution to journalArticle

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 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.

Original languageEnglish
Article numbere71
JournalBlood Cancer Journal
Volume2
Issue number5
DOIs
Publication statusPublished - Jun 2012

Keywords

  • Chronic myeloid leukemia
  • Oncogene
  • Transcription factor

ASJC Scopus subject areas

  • Oncology
  • Hematology

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    Manzotti, G., Mariani, S. A., Corradini, F., Bussolari, R., Cesi, V., Vergalli, J., Ferrari-Amorotti, G., Fragliasso, V., Soliera, A. R., Cattelani, S., Raschellà, G., Holyoake, T. L., & Calabretta, B. (2012). Expression of p89 c-Mybex9b, an alternatively spliced form of c-Myb, is required for proliferation and survival of p210BCR/ABL-expressing cells. Blood Cancer Journal, 2(5), [e71]. https://doi.org/10.1038/bcj.2012.16