title: STAT3 mutations identified in human hematologic neoplasms induce myeloid malignancies in a mouse bone marrow transplantation model.
abstract: STAT3 protein phosphorylation is a frequent event in various hematologic malignancies and solid tumors. Acquired STAT3 mutations have been recently identified in 40% of patients with T-cell large granular lymphocytic leukemia, a rare T-cell disorder. In this study, we investigated the mutational status of STAT3 in a large series of patients with lymphoid and myeloid diseases. STAT3 mutations were identified in 1.6% (4 of 258) of patients with T-cell neoplasms, in 2.5% (2 of 79) of patients with diffuse large B-cell lymphoma but in no other B-cell lymphoma patients (0 of 104) or patients with myeloid malignancies (0 of 96). Functional in vitro assays indicated that the STAT3Y640F mutation leads to a constitutive phosphorylation of the protein. STA21, a STAT3 small molecule inhibitor, inhibited the proliferation of two distinct STAT3 mutated cell lines. Using a mouse bone marrow transplantation assay, we observed that STAT3Y640F expression leads to the development of myeloproliferative neoplasms with expansion of either myeloid cells or megakaryocytes. Together, these data indicate that the STAT3Y640F mutation leads to constitutive activation of STAT3, induces malignant hematopoiesis in vivo, and may represent a novel therapeutic target in some lymphoid malignancies.
authors.affiliation: thomas.mercher@inserm.fr.
authors.forename: Lucile
authors.initials: L
authors.lastname: Couronné
authors.forename: Laurianne
authors.initials: L
authors.lastname: Scourzic
authors.forename: Camilla
authors.initials: C
authors.lastname: Pilati
authors.forename: Véronique
authors.initials: V
authors.lastname: Della Valle
authors.forename: Yannis
authors.initials: Y
authors.lastname: Duffourd
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Merlio
authors.forename: Marie
authors.initials: M
authors.lastname: Beylot-Barry
authors.forename: Frederik
authors.initials: F
authors.lastname: Damm
authors.forename: Marc-Henri
authors.initials: MH
authors.lastname: Stern
authors.forename: Philippe
authors.initials: P
authors.lastname: Gaulard
authors.forename: Laurence
authors.initials: L
authors.lastname: Lamant
authors.forename: Eric
authors.initials: E
authors.lastname: Delabesse
authors.forename: Hélène
authors.initials: H
authors.lastname: Merle-Beral
authors.forename: Florence
authors.initials: F
authors.lastname: Nguyen-Khac
authors.forename: Michaëla
authors.initials: M
authors.lastname: Fontenay
authors.forename: Hervé
authors.initials: H
authors.lastname: Tilly
authors.forename: Christian
authors.initials: C
authors.lastname: Bastard
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
authors.forename: Olivier A
authors.initials: OA
authors.lastname: Bernard
authors.forename: Thomas
authors.initials: T
authors.lastname: Mercher
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D004195:Disease Models, Animal; D019337:Hematologic Neoplasms / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D020014:K562 Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D009196:Myeloproliferative Disorders / Q000175:diagnosis / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000235:genetics*
chemical_list: D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse