Contribution of JAK2 mutations to T-cell lymphoblastic lymphoma development View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2016-01

AUTHORS

A M Roncero, P López-Nieva, M A Cobos-Fernández, M Villa-Morales, L González-Sánchez, J L López-Lorenzo, P Llamas, C Ayuso, S M Rodríguez-Pinilla, M C Arriba, M A Piris, P Fernández-Navarro, A F Fernández, M F Fraga, J Santos, J Fernández-Piqueras

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. More... »

PAGES

94

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/leu.2015.202

    DOI

    http://dx.doi.org/10.1038/leu.2015.202

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1040379605

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/26216197


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