Roles of T875N somatic mutation in the activity, structural stability of JAK2 and the transformation of OCI-AML3 cells

Int J Biol Macromol. 2019 Sep 15:137:1030-1040. doi: 10.1016/j.ijbiomac.2019.07.065. Epub 2019 Jul 9.

Abstract

Activating mutations in JAK2 have been described in patients with various hematologic malignancies including acute myeloid leukemia (AML) and myeloproliferative neoplasms. However, mechanism of these mutations in JAK2's activity, structural stability and pathology of AML remains poorly understood. The JAK2 T875N somatic mutation has been detected in about 5.2% of AML patients. But the structural basis and mechanism of JAK2 T875N mutation in the pathology of AML is still unclear. Our results suggested that JAK2 T875N mutation disrupted the T875 and D873 interaction which destroyed the compact structure of JH1 domain, forced it into the active conformation, facilitated the entrance of substrate and thus led to JAK2 hyperactivation. Mutations (T875N, T875A, D873A and D873G) disrupted the T875 and D873 interaction enhanced JAK2's activity, decreased its structural stability and JH2 domain's activity which further enhanced JAK2's activity, while mutations (T875R, D873E, T875R/D873E) repaired this interaction displayed opposite results. Moreover, JAK2 T875N mutation enhanced the activity of JAK2-STAT5 pathway, promoted the proliferation and transformation of OCI-AML3 cells. This study provides clues in understanding structural basis of T875N mutation caused JAK2 hyperactivation and its roles in the pathology of AML.

Keywords: Acute myeloid leukemia; Constitutive activation; Janus kinase 2.

MeSH terms

  • Cell Differentiation / genetics
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cell Transformation, Neoplastic / genetics*
  • Enzyme Activation / genetics
  • Enzyme Stability / genetics
  • Humans
  • Janus Kinase 2 / chemistry
  • Janus Kinase 2 / genetics*
  • Janus Kinase 2 / metabolism*
  • Leukemia, Myeloid, Acute / pathology*
  • Models, Molecular
  • Mutation*
  • Protein Conformation

Substances

  • JAK2 protein, human
  • Janus Kinase 2