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

• Published in: Cancers Vol. 12; no. 1; p. 126
• Main Authors: Wang, T Tiffany, Yang, Jun, Dighe, Shubha, Schmachtenberg, Matthew W, Leigh, Nathan T, Farber, Emily, Onengut-Gumuscu, Suna, Feith, David J, Ratan, Aakrosh, Loughran, Jr, Thomas P, Olson, Thomas L
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 03.01.2020; MDPI
• Subjects: Adaptation; Anemia; Cytokines; Cytotoxicity; Disease; Genes; Genomes; Hematology; Janus kinase; Kinases; Leukemia; Lymphocytes; Mutation; Phosphorylation; Proteins; Spleen; Stat1 protein; Stat3 protein; Stat5 protein; Transplantation; Whole genome sequencing; leukemia; mutation; NK cells; RNK-16; JAK/STAT; activation; F344
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers12010126

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 F334, including a mutation in 1. Functional studies showed 1 Y1034C to be a somatic activating mutation that mediated increased STAT signaling, as assessed by phosphoprotein levels. Sanger sequencing of 1 in RNK-1, -3, -7, and -16 found only RNK-16 to harbor the Y1034C 1 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 1 mutation in a spontaneous LGL leukemia model that results in increased downstream STAT signaling.