Chemogenomic Landscape of <i>RUNX1</i>-mutated AML Reveals Importance of <i>RUNX1</i> Allele Dosage in Genetics and Glucocorticoid Sensitivity.

Abstract

<b>Purpose:</b><i>RUNX1</i>-mutated (<i>RUNX1</i>^mut) acute myeloid leukemia (AML) is associated with adverse outcome, highlighting the urgent need for a better genetic characterization of this AML subgroup and for the design of efficient therapeutic strategies for this disease. Toward this goal, we further dissected the mutational spectrum and gene expression profile of <i>RUNX1</i>^mut AML and correlated these results to drug sensitivity to identify novel compounds targeting this AML subgroup.<b>Experimental Design:</b> RNA-sequencing of 47 <i>RUNX1</i>^mut primary AML specimens was performed and sequencing results were compared to those of <i>RUNX1</i> wild-type samples. Chemical screens were also conducted using <i>RUNX1</i>^mut specimens to identify compounds selectively affecting the viability of <i>RUNX1</i>^mut AML.<b>Results:</b> We show that samples with no remaining <i>RUNX1</i> wild-type allele are clinically and genetically distinct and display a more homogeneous gene expression profile. Chemical screening revealed that most <i>RUNX1</i>^mut specimens are sensitive to glucocorticoids (GCs) and we confirmed that GCs inhibit AML cell proliferation through their interaction with the glucocorticoid receptor (GR). We observed that specimens harboring <i>RUNX1</i> mutations expected to result in low residual RUNX1 activity are most sensitive to GCs, and that coassociating mutations as well as GR levels contribute to GC sensitivity. Accordingly, acquired glucocorticoid sensitivity was achieved by negatively regulating <i>RUNX1</i> expression in human AML cells.<b>Conclusions:</b> Our findings show the profound impact of <i>RUNX1</i> allele dosage on gene expression profile and glucocorticoid sensitivity in AML, thereby opening opportunities for preclinical testing which may lead to drug repurposing and improved disease characterization. <i>Clin Cancer Res; 23(22); 6969-81. ©2017 AACR</i>.