title: STAT3 supports experimental K-RasG12D-induced murine myeloproliferative neoplasms dependent on serine phosphorylation.
abstract: Juvenile myelomonocytic leukemia, acute myeloid leukemia (AML), and other myeloproliferative neoplasms (MPNs) are genetically heterogeneous but frequently display activating mutations in Ras GTPases and activation of signal transducer and activator of transcription 3 (STAT3). Altered STAT3 activity is observed in up to 50% of AML correlating with poor prognosis. Activated STAT proteins, classically associated with tyrosine phosphorylation, support tumor development as transcription factors, but alternative STAT functions independent of tyrosine phosphorylation have been documented, including roles for serine-phosphorylated STAT3 in mitochondria supporting transformation by oncogenic Ras. We examined requirements for STAT3 in experimental murine K-Ras-dependent hematopoietic neoplasia. We show that STAT3 is phosphorylated on S727 but not Y705 in diseased animals. Moreover, a mouse with a point mutation abrogating STAT3 S727 phosphorylation displayed delayed onset and decreased disease severity with significantly extended survival. Activated K-Ras required STAT3 for cytokine-independent growth of myeloid progenitors in vitro, and mitochondrially restricted STAT3 and STAT3-Y705F, both transcriptionally inert mutants, supported factor-independent growth. STAT3 was dispensable for growth of normal or K-Ras-mutant myeloid progenitors in response to cytokines. However, abrogation of STAT3-S727 phosphorylation impaired factor-independent malignant growth. These data document that serine-phosphorylated mitochondrial STAT3 supports neoplastic hematopoietic cell growth induced by K-Ras.
authors.affiliation: Department of Pathology and NYU Cancer Institute, New York University School of Medicine, New York, NY.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Gough
authors.affiliation: Department of Pathology and NYU Cancer Institute, New York University School of Medicine, New York, NY.
authors.forename: Isabelle J
authors.initials: IJ
authors.lastname: Marié
authors.affiliation: Department of Pathology and NYU Cancer Institute, New York University School of Medicine, New York, NY.
authors.forename: Camille
authors.initials: C
authors.lastname: Lobry
authors.affiliation: Department of Pathology and NYU Cancer Institute, New York University School of Medicine, New York, NY.
authors.forename: Iannis
authors.initials: I
authors.lastname: Aifantis
authors.affiliation: Department of Pathology and NYU Cancer Institute, New York University School of Medicine, New York, NY.
authors.forename: David E
authors.initials: DE
authors.lastname: Levy
mesh_terms: D000483:Alleles; D000818:Animals; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D012694:Serine / Q000737:chemistry*; D013234:Stem Cells / Q000166:cytology; D014443:Tyrosine / Q000737:chemistry; D020703:ras GTPase-Activating Proteins / Q000378:metabolism
chemical_list: D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D020703:ras GTPase-Activating Proteins; D014443:Tyrosine; D012694:Serine; D016283:Proto-Oncogene Proteins p21(ras)