TY - JOUR
T1 - STAT3 mutations identified in human hematologic neoplasms induce myeloid malignancies in a mouse bone marrow transplantation model
AU - Couronné, Lucile
AU - Scourzic, Laurianne
AU - Pilati, Camilla
AU - Valle, Véronique Della
AU - Duffourd, Yannis
AU - Solary, Eric
AU - Vainchenker, William
AU - Merlio, Jean Philippe
AU - Beylot-Barry, Marie
AU - Damm, Frederik
AU - Stern, Marc Henri
AU - Gaulard, Philippe
AU - Lamant, Laurence
AU - Delabesse, Eric
AU - Merle-Beral, Hélène
AU - Nguyen-Khac, Florence
AU - Fontenay, Michaëla
AU - Tilly, Hervé
AU - Bastard, Christian
AU - Zucman-Rossi, Jessica
AU - Bernard, Olivier A.
AU - Mercher, Thomas
PY - 2013/11/1
Y1 - 2013/11/1
N2 - 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 STAT3Y640Fmutation leads to constitutive activation of STAT3, induces malignant hematopoiesis in vivo, and may represent a novel therapeutic target in some lymphoid malignancies.
AB - 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 STAT3Y640Fmutation leads to constitutive activation of STAT3, induces malignant hematopoiesis in vivo, and may represent a novel therapeutic target in some lymphoid malignancies.
UR - http://www.scopus.com/inward/record.url?scp=84887008705&partnerID=8YFLogxK
U2 - 10.3324/haematol.2013.085068
DO - 10.3324/haematol.2013.085068
M3 - Article
C2 - 23872306
AN - SCOPUS:84887008705
SN - 0390-6078
VL - 98
SP - 1748
EP - 1752
JO - Haematologica
JF - Haematologica
IS - 11
ER -