Elucidation of the Regulators of Malignant Stem Cells
Gregor Adams,
Assistant Professor,
University of Southern California
Cancer is a result of complex interactions between germline genetic susceptibility, oncogenic somatic mutations, and environmental insults, each of which contributes to the overall risk for an individual to develop the disease. However, the genetic drivers of malignant cell transformation, which act in cooperation with oncogenic mutations, are largely unknown. We have used a recently developed panel of ~100 classic inbred and recombinant inbred mouse strains, termed the Hybrid Mouse Diversity Panel (HMDP), to determine the variation in leukemic cell transformation by the Bcr-Abl oncogene as a function of genetic background. Our data demonstrate that oncogenic transformation under identical conditions varies by ~1000-fold across the HMDP. These observations were highly reproducible and provide strong evidence that genetic factors can modify Bcr-Abl-induced leukemogenesis. Using these data, we performed a genome-wide association study (GWAS) in the HMDP to identify the genetic modifiers of leukemogenesis. A statistically significant association (p=2.11x10-6) was observed with single-nucleotide polymorphisms (SNPs) within a small linkage disequilibrium (LD) block on chromosome 1. Highly significant cis eQTLs were also identified in multiple tissues in the HMDP, including macrophages (p=5.75x10-6), providing strong evidence for this region as a candidate that regulates leukemogenesis. We are currently further validating the function of this region in leukemogenesis using CRISPR-Cas9 mediated gene editing in CML cell lines. These data demonstrate the power of genetic screening to identify novel genetic modifiers of malignant stem cell pathophysiology and may lead to improved treatments for hematological malignancies through the development of novel therapeutic targets.
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