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.

Expression of p89(c-Mybex9b), an alternatively spliced form of c-Myb, is required for proliferation and survival of p210BCR/ABL-expressing cells / Manzotti, Gloria; Mariani, Sa; Corradini, Francesca; Bussolari, Rita; Cesi, V; Vergalli, J; Ferrari, Giovanna; Fragliasso, V; Soliera, Angela Rachele; Cattelani, Sara; Raschellà, G; Holyoake, Tl; Calabretta, Bruno. - In: BLOOD CANCER JOURNAL. - ISSN 2044-5385. - ELETTRONICO. - 5:(2012), pp. 1-11. [10.1038/bcj.2012.16]

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

MANZOTTI, GLORIA;CORRADINI, Francesca;BUSSOLARI, Rita;FERRARI, Giovanna;SOLIERA, Angela Rachele;CATTELANI, Sara;CALABRETTA, Bruno
2012

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.
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Expression of p89(c-Mybex9b), an alternatively spliced form of c-Myb, is required for proliferation and survival of p210BCR/ABL-expressing cells / Manzotti, Gloria; Mariani, Sa; Corradini, Francesca; Bussolari, Rita; Cesi, V; Vergalli, J; Ferrari, Giovanna; Fragliasso, V; Soliera, Angela Rachele; Cattelani, Sara; Raschellà, G; Holyoake, Tl; Calabretta, Bruno. - In: BLOOD CANCER JOURNAL. - ISSN 2044-5385. - ELETTRONICO. - 5:(2012), pp. 1-11. [10.1038/bcj.2012.16]
Manzotti, Gloria; Mariani, Sa; Corradini, Francesca; Bussolari, Rita; Cesi, V; Vergalli, J; Ferrari, Giovanna; Fragliasso, V; Soliera, Angela Rachele; Cattelani, Sara; Raschellà, G; Holyoake, Tl; Calabretta, Bruno
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/793089
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