{"doi":"10.1038/s41375-024-02456-8","title":"miR-196b-Oct1/2 axis regulates DNMT3A-mutant AML pathogenesis","abstract":"Somatic mutations in the de novo DNA methyltransferase DNMT3A occur in approximately one-third of cytogenetically normal acute myeloid leukemia (AML) [ 1 ]. DNMT3A mutations result in global DNA hypomethylation, consistent with DNMT3A loss-of-function, and abnormal self-renewal of hematopoietic stem cells [ 2 ]. While DNA hypomethylation is reversible and required to maintain the leukemogenic potential of DNMT3A -mutant AML cells [ 3 ], the loss of Dnmt3a alone is not sufficient for leukemic transformation of normal hematopoietic stem and progenitor cells in mice [ 4 ]. In AML, mutations in epigenetic modifiers are almost exclusively found with additional genetic lesions. Constitutive activating mutations in the receptor tyrosine kinase FLT3 , commonly internal tandem duplications (ITD) that result in ligand-independent receptor activation, frequently co-occur with DNMT3A mutations [ 1 , 5 ]. Consistent with this, we previously reported that mice with combined somatic loss of Dnmt3a and germline knock-in of Flt3 ITD ( Dnmt3a +/- Flt3 ITD ) develop fully penetrant, transplantable, lethal AML [ 3 ]. However, identification of therapeutically targetable pathways in DNMT3A -mutant AML remain a major challenge as differences in DNA methylation have only modest concordance with protein-coding gene expression. Deregulation of microRNA (miRNA) is a common pathogenic mechanism in human malignancies, including AML [ 6 ]. We previously reported that miR-196b is hypomethylated and overexpressed in human and murine DNMT3A -mutant AML and is associated with poor survival [ 7 ]. We discovered that miR-196b mediated repression of Toll-like-receptor (TLR) signaling is important for DNMT3A -mutant human AML and Dnmt3a +/- Flt3 ITD murine AML by dampening the ability of AML cells to mature in response to TLR stimuli [ 7 ]. However, whether miR-196b is required for leukemia initiation and development by somatic DNMT3A loss-of-function mutations is not known. To investigate the role of miR-196b in leukemia initiation by mutant Dnmt3a , we generated Dnmt3a +/– Flt3 ITD mice with germline deletion of miR-196b [ 8 ] ( miR196b –/– Dnmt3a +/– Flt3 ITD ). The deletion is specific to miR-196b and does not significantly alter miR-196a expression (Fig. 1A ). Of note, miR-196b deletion alone does not perturb normal steady state hematopoiesis in mice (Supplementary Fig. 1A–H ). As previously reported, Dnmt3a +/- Flt3 ITD mice develop AML [ 3 ] as evidenced by increased immature forms in the bone marrow and myeloblastic infiltration in liver and spleen as compared to wild-type control mice (Fig. 1B ). miR196b -/- Dnmt3a +/- Flt3 ITD mice also develop AML with significantly shorter latency compared to Dnmt3a +/– Flt3 ITD control mice with median survivals of 33 days and 41 days, respectively (Fig. 1B-C ). Spleen size and weight were increased in moribund miR196b –/– Dnmt3a +/– Flt3 ITD as compared to age-matched Dnmt3a +/- Flt3 ITD mice (Fig. 1D, E ), indicative of accelerated leukemia development. Flow cytometric analyses comparing leukemic stem/progenitor cells isolated from the bone marrow and spleens of moribund miR196b –/– Dnmt3a +/– Flt3 ITD and Dnmt3a +/– Flt3 ITD mice revealed a significant decrease in the total number of lineage negative (Lin - ) cells in the bone marrow but not the spleen (Fig. 1F, G ). No significant differences in the proportion of immunophenotypic common myeloid progenitor (CMP), granulocyte-monocyte progenitor (GMP), or megakaryocyte-erythroid progenitor (MEP) cells were detected in the bone marrow or spleens from moribund-matched miR196b –/– Dnmt3a +/– Flt3 ITD and Dnmt3a +/– Flt3 ITD mice (Fig. 1F, G ). The proportion of leukemic Lin - Sca1 + c-Kit + (LSK) cells was significantly increased in the bone marrow, but not spleens of moribund miR196b –/– Dnmt3a +/- Flt3 ITD mice compared to Dnmt3a +/- Flt3 ITD controls (Fig. 1F, G ). These data are consistent with accelerated leukemia development in miR196b –/– Dnmt3a +/– Flt3 ITD co","journal":"Leukemia","year":2024,"id":474567,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9428,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":910988,"name":"Melanie L. Goetz","orcid":"0000-0001-9584-8634","position":1,"is_corresponding":false},{"id":910986,"name":"Jennifer S. Romer-Seibert","orcid":"0000-0001-5607-5114","position":2,"is_corresponding":false},{"id":910985,"name":"Holly A. Gamlen","orcid":"0000-0002-3746-2909","position":3,"is_corresponding":false},{"id":689586,"name":"Edwina McGlinn","orcid":"0000-0002-1829-986X","position":4,"is_corresponding":false},{"id":638816,"name":"Sara E. Meyer","orcid":"0000-0003-2930-748X","position":5,"is_corresponding":false},{"id":910987,"name":"Michael Lawler","orcid":"0000-0002-8787-6616","position":0,"is_corresponding":true}],"reference_count":15,"raw_metadata":null,"created_at":"2026-07-19T02:06:13.042906Z","pmid":"39580581","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":[]}