| First Author | Khanna-Gupta A | Year | 2012 |
| Journal | J Biol Chem | Volume | 287 |
| Issue | 39 | Pages | 32728-37 |
| PubMed ID | 22851180 | Mgi Jnum | J:192968 |
| Mgi Id | MGI:5467170 | Doi | 10.1074/jbc.M112.373274 |
| Citation | Khanna-Gupta A, et al. (2012) Up-regulation of translation eukaryotic initiation factor 4E in nucleophosmin 1 haploinsufficient cells results in changes in CCAAT enhancer-binding protein alpha activity: implications in myelodysplastic syndrome and acute myeloid leukemia. J Biol Chem 287(39):32728-37 |
| abstractText | NPM1 is a ubiquitously expressed nucleolar phosphoprotein, the gene for which maps to chromosome 5q35 in close proximity to a commonly deleted region associated with (del)5q, a type of myelodysplastic syndrome (MDS). This region is also a frequent target of deletions in de novo and therapy-related MDS/acute myeloid leukemia. Previous studies have shown that Npm1(+/-) mice develop an MDS-like disease that transforms to acute myeloid leukemia over time. To better understand the mechanism by which NPM1 haploinsufficiency causes an MDS phenotype, we generated factor-dependent myeloid cell lines from the bone marrow of Npm1(+/+) and Npm1(+/-) mice and demonstrated compromised neutrophil-specific gene expression in the MNPM1(+/-) cells. We attribute these observations to increased levels of the shorter, dominant negative leukemogenic isoform (p30) of CCAAT enhancer-binding protein alpha (C/EBPalpha). We show that this increase is caused, in part, by elevated levels of the activated translation initiation factor eIF4E, overexpression of which also increases translation of C/EBPalphap30 in HEK293 cells. In a positive feedback loop, eIF4E expression is further elevated both at the mRNA and protein levels by C/EBPalphap30 but not by the full-length C/EBPalphap42. Re-expression of C/EBPalphap42 or NPM1 but not C/EBPalphap30 in MNPM1(+/-) cells partially rescues the myeloid phenotype. Our observations suggest that the aberrant feed-forward pathway that keeps eIF4E and C/EBPalphap30 elevated in NPM1(+/-) cells contributes to the MDS phenotype associated with NPM1 deficiency. |
