Up-regulation of translation eukaryotic initiation factor 4E in nucleophosmin 1 haploinsufficient cells results in changes in CCAAT enhancer-binding protein α activity: implications in myelodysplastic syndrome and acute myeloid leukemia

• Published in: The Journal of biological chemistry 2012-09, Vol.287 (39), p.32728-32737
• Main Authors: Khanna-Gupta, Arati, Abayasekara, Nirmalee, Levine, Michelle, Sun, Hong, Virgilio, Maria, Nia, Navid, Halene, Stephanie, Sportoletti, Paolo, Jeong, Jee-Yeong, Pandolfi, Pier Paolo, Berliner, Nancy
• Format: Article
• Language: English
• Subjects: Animals; CCAAT-Enhancer-Binding Proteins - genetics; CCAAT-Enhancer-Binding Proteins - metabolism; Eukaryotic Initiation Factor-4E - biosynthesis; Eukaryotic Initiation Factor-4E - genetics; Gene Expression Regulation, Leukemic; Haploinsufficiency; HEK293 Cells; Humans; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Mice; Mice, Mutant Strains; Molecular Bases of Disease; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - metabolism; Myelodysplastic Syndromes - pathology; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Protein Isoforms - genetics; Protein Isoforms - metabolism; Up-Regulation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.373274

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 α (C/EBPα). 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/EBPαp30 in HEK293 cells. In a positive feedback loop, eIF4E expression is further elevated both at the mRNA and protein levels by C/EBPαp30 but not by the full-length C/EBPαp42. Re-expression of C/EBPαp42 or NPM1 but not C/EBPαp30 in MNPM1(+/-) cells partially rescues the myeloid phenotype. Our observations suggest that the aberrant feed-forward pathway that keeps eIF4E and C/EBPαp30 elevated in NPM1(+/-) cells contributes to the MDS phenotype associated with NPM1 deficiency.