| First Author | Barreyro L | Year | 2024 |
| Journal | iScience | Volume | 27 |
| Issue | 6 | Pages | 109809 |
| PubMed ID | 38784013 | Mgi Jnum | J:349370 |
| Mgi Id | MGI:7642672 | Doi | 10.1016/j.isci.2024.109809 |
| Citation | Barreyro L, et al. (2024) Dysregulated innate immune signaling cooperates with RUNX1 mutations to transform an MDS-like disease to AML. iScience 27(6):109809 |
| abstractText | 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. |
