STAT3 mutations identified in human hematologic neoplasms induce myeloid malignancies in a mouse bone marrow transplantation model

Haematologica. 2013 Nov;98(11):1748-52. doi: 10.3324/haematol.2013.085068. Epub 2013 Jul 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Transplantation / adverse effects*
  • Disease Models, Animal*
  • Hematologic Neoplasms / diagnosis
  • Hematologic Neoplasms / genetics*
  • Humans
  • K562 Cells
  • Mice
  • Mice, Inbred C57BL
  • Mutation / genetics*
  • Myeloproliferative Disorders / diagnosis
  • Myeloproliferative Disorders / genetics*
  • STAT3 Transcription Factor / genetics*

Substances

  • STAT3 Transcription Factor
  • Stat3 protein, mouse