title: 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.
abstract: 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.
authors.affiliation: Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. akhanna-gupta@partners.org
authors.forename: Arati
authors.initials: A
authors.lastname: Khanna-Gupta
authors.forename: Nirmalee
authors.initials: N
authors.lastname: Abayasekara
authors.forename: Michelle
authors.initials: M
authors.lastname: Levine
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.forename: Maria
authors.initials: M
authors.lastname: Virgilio
authors.forename: Navid
authors.initials: N
authors.lastname: Nia
authors.forename: Stephanie
authors.initials: S
authors.lastname: Halene
authors.forename: Paolo
authors.initials: P
authors.lastname: Sportoletti
authors.forename: Jee-Yeong
authors.initials: JY
authors.lastname: Jeong
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: Nancy
authors.initials: N
authors.lastname: Berliner
mesh_terms: D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D039561:Eukaryotic Initiation Factor-4E / Q000096:biosynthesis* / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D057895:Haploinsufficiency; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000090243:Nucleophosmin; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C530718:CEBPA protein, mouse; D039561:Eukaryotic Initiation Factor-4E; C000716967:NPM1 protein, human; D009363:Neoplasm Proteins; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D020033:Protein Isoforms; D000090243:Nucleophosmin