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

11 Citations (Scopus)

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

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K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Protein Isoforms
myb Genes
Myeloid Progenitor Cells
Proteins
Cell Lineage
Exons
Down-Regulation
Amino Acids
Imatinib Mesylate
Ectopic Gene Expression

Keywords

  • Chronic myeloid leukemia
  • Oncogene
  • Transcription factor

ASJC Scopus subject areas

  • Oncology
  • Hematology

Cite this

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

In: Blood Cancer Journal, Vol. 2, No. 5, e71, 06.2012.

Research output: Contribution to journalArticle

Manzotti, G, Mariani, SA, Corradini, F, Bussolari, R, Cesi, V, Vergalli, J, Ferrari-Amorotti, G, Fragliasso, V, Soliera, AR, Cattelani, S, Raschellà, G, Holyoake, TL & 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, vol. 2, no. 5, e71. https://doi.org/10.1038/bcj.2012.16
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. / Expression of p89 c-Mybex9b, an alternatively spliced form of c-Myb, is required for proliferation and survival of p210BCR/ABL-expressing cells. In: Blood Cancer Journal. 2012 ; Vol. 2, No. 5.
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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.",
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AU - Bussolari, R.

AU - Cesi, V.

AU - Vergalli, J.

AU - Ferrari-Amorotti, G.

AU - Fragliasso, V.

AU - Soliera, A. R.

AU - Cattelani, S.

AU - Raschellà, G.

AU - Holyoake, T. L.

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