Contribution of JAK2 mutations to T-cell lymphoblastic lymphoma development

Leukemia. 2016 Jan;30(1):94-103. doi: 10.1038/leu.2015.202. Epub 2015 Jul 28.

Abstract

The JAK-STAT pathway has a substantial role in lymphoid precursor cell proliferation, survival and differentiation. Nonetheless, the contribution of JAK2 to T-cell lymphoblastic lymphoma (T-LBL) development remains poorly understood. We have identified one activating TEL-JAK2 translocation and four missense mutations accumulated in 2 out of 16 T-LBL samples. Two of them are novel JAK2 mutations and the other two are reported for the first time in T-LBL. Notably, R683G and I682T might have arisen owing to RNA editing. Mutated samples showed different mutated transcripts suggesting sub-clonal heterogeneity. Functional approaches revealed that two JAK2 mutations (H574R and R683G) constitutively activate JAK-STAT signaling in γ2A cells and can drive the proliferation of BaF3-EpoR cytokine-dependent cell line. In addition, aberrant hypermethylation of SOCS3 might contribute to enhance the activation of JAK-STAT signaling. Of utmost interest is that primary T-LBL samples harboring JAK2 mutations exhibited increased expression of LMO2, suggesting a mechanistic link between JAK2 mutations and the expression of LMO2, which was confirmed for the four missense mutations in transfected γ2A cells. We therefore propose that active JAK2 contribute to T-LBL development by two different mechanisms, and that the use of pan-JAK inhibitors in combination with epigenetic drugs should be considered in future treatments.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Chromosomes, Human, Pair 12
  • Chromosomes, Human, Pair 9
  • DNA Methylation
  • Humans
  • Janus Kinase 2 / genetics*
  • Janus Kinase 2 / physiology
  • LIM Domain Proteins / genetics
  • Mutation*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Proto-Oncogene Proteins / genetics
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins / genetics
  • Translocation, Genetic

Substances

  • Adaptor Proteins, Signal Transducing
  • LIM Domain Proteins
  • LMO2 protein, human
  • Proto-Oncogene Proteins
  • SOCS3 protein, human
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • JAK2 protein, human
  • Janus Kinase 2