NF?B1-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 NF?B and Flt3 are frequently detected, and dual IKK2/Flt3 inhibitor regimes are used for treatment. However, how NF?B 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 NF?B signaling system elevates basal nuclear NF?B, where RelA:p52 drives Sod2 expression and enables prolonged progenitor proliferation. Our work reveals how the inflammation response NF?B system controls in stress-responsive myelopoiesis, and how system imbalances can contribute to the pathogenesis of myeloid neoplasms. Overall design: To investigate the interplay between RelA and p50 during BMDC differentation, we generated RNA-seq in Flt3 differeniating BMDCs in both wild-type and Nfkb1-/- cells.