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

• DOI: 10.1158/1078-0432.c.6532769.v1
• Publication Date: 2023-04-01T05:59:53Z
• Authors: Holly A. Gamlen; Jennifer S. Romer...; Michael E. Lawler; Amanda M. Versace; Melanie L. Goetz; Yang Feng; Olga A. Guryanova; Neil Palmisiano; Sara E. Meyer

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