Dysregulated innate immune signaling cooperates with RUNX1 mutations to transform an MDS-like disease to AML

Dysregulated innate immune signaling is linked to preleukemic conditions and myeloid malignancies. However, it is unknown whether sustained innate immune signaling contributes to malignant transformation. Here we show that cell-intrinsic innate immune signaling driven by miR-146a deletion (miR-146a^KO), a commonly deleted gene in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), cooperates with mutant RUNX1 (RUNX1^mut) to initially induce marrow failure and features of MDS. However, miR-146a^KO hematopoietic stem and/or progenitor cells (HSPCs) expressing RUNX1^mut eventually progress to a fatal AML. miR-146a^KO HSPCs exhaust during serial transplantation, while expression of RUNX1^mut restored their hematopoietic cell function. Thus, HSPCs exhibiting dysregulated innate immune signaling require a second hit to develop AML. Inhibiting the dysregulated innate immune pathways with a TRAF6-UBE2N inhibitor suppressed leukemic miR-146a^KO/RUNX1^mut HSPCs, highlighting the necessity of TRAF6-dependent cell-intrinsic innate immune signaling in initiating and maintaining AML. These findings underscore the critical role of dysregulated cell-intrinsic innate immune signaling in driving preleukemic cells toward AML progression.