Data from miR-196b–TLR7/8 Signaling Axis Regulates Innate Immune Signaling and Myeloid Maturation in <i>DNMT3A</i>-Mutant AML

Abstract

<div>AbstractPurpose:<p><i>DNMT3A</i> mutations confer a poor prognosis in acute myeloid leukemia (AML), but the molecular mechanisms downstream of <i>DNMT3A</i> mutations in disease pathogenesis are not completely understood, limiting targeted therapeutic options. The role of miRNA in <i>DNMT3A</i>-mutant AML pathogenesis is understudied.</p>Experimental Design:<p>DNA methylation and miRNA expression was evaluated in human AML patient samples and in <i>Dnmt3a/Flt3</i>-mutant AML mice. The treatment efficacy and molecular mechanisms of TLR7/8-directed therapies on <i>DNMT3A</i>-mutant AML were evaluated <i>in vitro</i> on human AML patient samples and in <i>Dnmt3a/Flt3</i>-mutant AML mice.</p>Results:<p>miR-196b is hypomethylated and overexpressed in <i>DNMT3A</i>-mutant AML and is associated with poor patient outcome. miR-196b overexpression in <i>DNMT3A</i>-mutant AML is important to maintain an immature state and leukemic cell survival through repression of TLR signaling. The TLR7/8 agonist resiquimod induces dendritic cell–like differentiation with costimulatory molecule expression in <i>DNMT3A</i>-mutant AML cells and provides a survival benefit to <i>Dnmt3a/Flt3</i>-mutant AML mice. The small molecule bryostatin-1 augments resiquimod-mediated AML growth inhibition and differentiation.</p>Conclusions:<p><i>DNMT3A</i> loss-of-function mutations cause miRNA locus-specific hypomethylation and overexpression important for mutant <i>DNMT3A</i>–mediated pathogenesis and clinical outcomes. Specifically, the overexpression of miR-196b in <i>DNMT3A</i>-mutant AML creates a novel therapeutic vulnerability by controlling sensitivity to TLR7/8-directed therapies.</p></div>