Abstract 2063: A novel ELAVL1-TYK2 fusion protein drives STAT3/5 activation and PIM-1 expression, survival and growth in the MOLM-16 acute myeloid leukemia cell line

Abstract

Abstract Pim kinases are upregulated in leukemias and lymphomas and mediate cell growth and survival. Acute myeloid leukemia cell lines sensitive to the pan-Pim kinase inhibitor AZD1208 showed elevated pSTAT5 and Pim-1 expression that correlated with known tyrosine kinase mutations. However, one of the most sensitive lines, MOLM-16, lacked a reported driver mutation. RNA transcriptome sequencing identified a novel fusion gene comprised of the TYK2 kinase domain fused to the N-terminus of the RNA binding protein ELAVL1/HuR. The genes are co-localized within ∼2 MB on the short arm of chromosome 19, at position 13.2. The fusion results in loss of the Tyk2 pseudokinase domain, which negatively regulates kinase activity, suggesting a gain of function genetic alteration. Tyk2 was highly expressed and found to be amplified in MOLM-16 cells, with a higher degree of amplification of the exons encoding the kinase domain. Knockdown experiments demonstrated that down-regulation of the fusion gene, but not of the wild type ELAVL1 or TYK2 transcripts, resulted in suppression of STAT3/5 phosphorylation, Pim1 levels, and proliferation. Conversely, expression of the ELAVL1-TYK2 fusion protein in FDCP1 cells was shown to confer IL-3 independent growth. The fusion was not identified in screening of ∼200 AML patient samples or through analysis of TCGA data suggesting that it occurs at a low frequency, but interestingly NPM1-Tyk2 fusions have recently been described in cutaneous CD30-positive lymphoproliferative disorders (Velusamy et al. Blood 2014). Citation Format: Kristen McEachern, Erika Keeton, Keith Dillman, Minwei Ye, Chloe Stengel, Huawei Chen, Suping Wang, Shaun Grosskurth, Rosemary E. Gale, David C. Linch, Asim Khwaja, Zhongwu Lai, Dennis Huszar. A novel ELAVL1-TYK2 fusion protein drives STAT3/5 activation and PIM-1 expression, survival and growth in the MOLM-16 acute myeloid leukemia cell line. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2063. doi:10.1158/1538-7445.AM2015-2063