{"doi":"10.1158/1078-0432.c.6532769.v1","title":"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>","journal":null,"year":2023,"id":405001,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9386,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":910986,"name":"Jennifer S. Romer-Seibert","orcid":"0000-0001-5607-5114","position":1,"is_corresponding":false},{"id":910987,"name":"Michael Lawler","orcid":"0000-0002-8787-6616","position":2,"is_corresponding":false},{"id":786770,"name":"Amanda M. Versace","orcid":"0000-0003-0067-0365","position":3,"is_corresponding":false},{"id":910988,"name":"Melanie L. Goetz","orcid":"0000-0001-9584-8634","position":4,"is_corresponding":false},{"id":589287,"name":"Yang Feng","orcid":"0000-0002-9533-1501","position":5,"is_corresponding":false},{"id":589288,"name":"Olga A. Guryanova","orcid":"0000-0002-6514-8466","position":6,"is_corresponding":false},{"id":262222,"name":"Neil Palmisiano","orcid":"0000-0003-1524-8108","position":7,"is_corresponding":false},{"id":638816,"name":"Sara E. Meyer","orcid":"0000-0003-2930-748X","position":8,"is_corresponding":false},{"id":910985,"name":"Holly A. Gamlen","orcid":"0000-0002-3746-2909","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-19T01:20:49.237119Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}