先天免疫信号失调与白血病前期病症和骨髓恶性肿瘤有关。然而，尚不清楚持续的先天免疫信号是否有助于恶性转化。在这里，我们表明，由 miR-146a 缺失（miR-146aKO）（骨髓增生异常综合征（MDS）和急性髓性白血病（AML）中常见的缺失基因）驱动的细胞固有先天免疫信号与突变体 RUNX1（RUNX1mut）合作，最初诱导骨髓衰竭和 MDS 的特征。然而，表达 RUNX1mut 的 miR-146aKO 造血干细胞和/或祖细胞 (HSPC) 最终进展为致命的 AML。 miR-146aKO HSPC 在连续移植过程中耗尽，而 RUNX1mut 的表达恢复了其造血细胞功能。因此，表现出失调的先天免疫信号传导的 HSPC 需要第二次打击才能发展为 AML。使用 TRAF6-UBE2N 抑制剂抑制失调的先天免疫通路可抑制白血病 miR-146aKO/RUNX1mut HSPC，这凸显了 TRAF6 依赖性细胞内在先天免疫信号在启动和维持 AML 中的必要性。这些发现强调了细胞内在先天免疫信号失调在驱动白血病前期细胞进展为 AML 方面的关键作用。© 2024 作者。

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-146aKO), a commonly deleted gene in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), cooperates with mutant RUNX1 (RUNX1mut) to initially induce marrow failure and features of MDS. However, miR-146aKO hematopoietic stem and/or progenitor cells (HSPCs) expressing RUNX1mut eventually progress to a fatal AML. miR-146aKO HSPCs exhaust during serial transplantation, while expression of RUNX1mut 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-146aKO/RUNX1mut 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.© 2024 The Author(s).