Abstract 2893: Sleeping Beauty uncovers cooperating driver genes in a preclinical mouse model of myeloid leukemia

• DOI: 10.1158/1538-7445.am2015-2893
• Publication Date: 2015-08-05T01:32:19Z
• Authors: Karen M. Mann; Justin Newberg; Nicholas Navin; David J. Adams; Nancy Jenkins; Neal Copeland; Michael B. Mann
• Keywords: 0301 basic medicine; 03 medical and health sciences; 3. Good health

Abstract Myeloid leukemia is associated with few predominant mutations and translocations in humans. In order to uncover additional loci that drive the disease, we developed an aggressive, fully-penetrant mouse model of myeloid using Sleeping Beauty insertional mutagenesis. Animals distinct foci expanded splenic red pulp as early 30 days age had a median survival 70 days. SB insertions sequenced from 168 spleens mice end-stage disease revealed more than 470 statistically defined candidate cancer genes (CCGs), 87 which have orthologs mutated human AML. Pathway enrichment analysis CCGs confirmed MAP kinase Jak-Stat signaling play important role disease. Twenty-five were trunk drivers based on high sequence read representation multiple tumors population. Among was suite transcription factors act downstream signaling, including Ets- family member Erg, Ets1 Fli1. We single cells isolated tumor interrogate cooperating relationships among drivers. Hierarchical clustering intra-tumor heterogeneity identified three subclonal populations. Importantly, Erg Ghr anchored one subpopulation second by Notch1. These gene observed population-based statistical cooperativity between Notch1 cohort tumors. Mutual-exclusivity for driving supported microarray expression subset RNA-seq many divers Ghr, Chimeric transcripts four driver contained splice donor wild type exons encoding functional domains translated proteins, suggesting drives mis-expression these proteins induce leukemia. new contribute progression gained insight into both inter- intra- this type. SB-driven robust, transplantable genetic offers unique platform preclinical testing. Transposon insertion profiles provide powerful means stratify targeted therapies. Finally, can be harnessed confer therapy response or resistance. Citation Format: Karen M. Mann, Justin Newberg, Nicholas Navin, David J. Adams, Nancy Jenkins, Neal Copeland, Michael B. Mann. uncovers [abstract]. In: Proceedings 106th Annual Meeting American Association Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Res 2015;75(15 Suppl):Abstract nr 2893. doi:10.1158/1538-7445.AM2015-2893