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Whole Genome Sequencing of Spontaneously Occurring Rat Natural Killer Large Granular Lymphocyte Leukemia Identifies JAK1 Somatic Activating Mutation

1
Department of Medicine and University of Virginia Cancer Center, Division of Hematology & Oncology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
2
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(1), 126; https://doi.org/10.3390/cancers12010126
Received: 15 November 2019 / Revised: 20 December 2019 / Accepted: 25 December 2019 / Published: 3 January 2020
(This article belongs to the Special Issue JAK-STAT Signalling Pathway in Cancer)
Large granular lymphocyte (LGL) leukemia arises spontaneously in elderly Fischer (F344) rats. This rodent model has been shown to emulate many aspects of the natural killer (NK) variant of human LGL leukemia. Previous transplantation of leukemic material into young F344 rats resulted in several strains of rat NK (RNK) primary leukemic cells. One strain, RNK-16, was adapted into the RNK-16 cell line and established as an aggressive NK-LGL leukemia model. Whole genome sequencing of the RNK-16 cell line identified 255,838 locations where the RNK16 had an alternate allele that was different from F344, including a mutation in Jak1. Functional studies showed Jak1 Y1034C to be a somatic activating mutation that mediated increased STAT signaling, as assessed by phosphoprotein levels. Sanger sequencing of Jak1 in RNK-1, -3, -7, and -16 found only RNK-16 to harbor the Y1034C Jak1 mutation. In vivo studies revealed that rats engrafted with RNK-16 primary material developed leukemia more rapidly than those engrafted with RNK-1, -3, and -7. Additionally, ex vivo RNK-16 spleen cells from leukemic rats exhibited increased STAT1, STAT3, and STAT5 phosphorylation compared to other RNK strains. Therefore, we report and characterize a novel gain-of-function Jak1 mutation in a spontaneous LGL leukemia model that results in increased downstream STAT signaling. View Full-Text
Keywords: JAK/STAT; leukemia; mutation; RNK-16; F344; NK cells; activation JAK/STAT; leukemia; mutation; RNK-16; F344; NK cells; activation
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Wang, T.T.; Yang, J.; Dighe, S.; Schmachtenberg, M.W.; Leigh, N.T.; Farber, E.; Onengut-Gumuscu, S.; Feith, D.J.; Ratan, A.; Loughran, T.P., Jr.; Olson, T.L. Whole Genome Sequencing of Spontaneously Occurring Rat Natural Killer Large Granular Lymphocyte Leukemia Identifies JAK1 Somatic Activating Mutation. Cancers 2020, 12, 126.

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