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 language | English |
|---|---|
| Article number | e71 |
| Journal | Blood Cancer Journal |
| Volume | 2 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - Jun 2012 |
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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 journal › Article
}
TY - JOUR
T1 - Expression of p89 c-Mybex9b, an alternatively spliced form of c-Myb, is required for proliferation and survival of p210BCR/ABL-expressing cells
AU - Manzotti, G.
AU - Mariani, S. A.
AU - Corradini, F.
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.
AU - Calabretta, B.
PY - 2012/6
Y1 - 2012/6
N2 - 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.
AB - 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.
KW - Chronic myeloid leukemia
KW - Oncogene
KW - Transcription factor
UR - http://www.scopus.com/inward/record.url?scp=84864046723&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84864046723&partnerID=8YFLogxK
U2 - 10.1038/bcj.2012.16
DO - 10.1038/bcj.2012.16
M3 - Article
VL - 2
JO - Blood Cancer Journal
JF - Blood Cancer Journal
SN - 2044-5385
IS - 5
M1 - e71
ER -