NFκB1-deficiency associated with Flt3-myeloid leukemia enhances the self-renewal capacity via dysregulated RelA:p52 and SOD2 expression

In acute myeloid leukemia (AML), abnormal expression of NFκB and Flt3 are frequently detected, and dual IKK2/Flt3 inhibitor regimes are used for treatment. However, how NFκB is involved in Flt3-driven myelopoiesis remains unknown. We report that AML is associated with reduced expression of NFKB1, and that Nfkb1 deficiency conveys poor survival in a mouse Flt3-ITD-driven myeloid leukemia model. Interpreting myelopoiesis dynamics with mathematical modeling suggests that Nfkb1-/- hematopoietic stem and progenitor cells possess enhanced self-renewal and are skewed towards plasmacytoid dendritic cells. Single-cell RNA-seq confirmed this interpretation via pseudotime analysis and gene signatures indicating stemness and pDC priming. Biochemical analysis and genetic rescues demonstrate how an imbalanced NFκB signaling system elevates basal nuclear NFκB, where RelA:p52 drives Sod2 expression and enables prolonged progenitor proliferation. Our work reveals how the inflammation response NFκB system controls in stress-responsive myelopoiesis, and how system imbalances can contribute to the pathogenesis of myeloid neoplasms.