In vivo ablation of NF-κB cascade effectors alleviates disease burden in myeloproliferative neoplasms

• Abrogation of RelA, Myd88, and IRAK4 consistently suppressed disease hallmarks of leukocytosis, splenomegaly, and bone marrow dysfunction.

• IRAK4 inhibitor CA-4948 effectively reduced leukemic engraftment of PDX models of myelofibrosis.

Hyperactivation of the NF-κB cascade propagates oncogenic signaling and proinflammation, which together augments disease burden in myeloproliferative neoplasms (MPNs). Here, we systematically ablate NF-κB signaling effectors to identify core dependencies using a series of primary samples and syngeneic and patient–derived xenograft (PDX) mouse models. Conditional knockout of Rela attenuated Jak2^V617F- and MPL^W515L-driven onset of polycythemia vera and myelofibrosis disease hallmarks, respectively. In PDXs, RELA knockout diminished leukemic engraftment and bone marrow fibrosis while extending survival. Knockout of upstream effector Myd88 also alleviated disease burden; conversely, perturbation of negative regulator miR-146a microRNA induced earlier lethality and exacerbated disease. Perturbation of NF-κB effectors further skewed the abundance and distribution of hematopoietic multipotent progenitors. Finally, pharmacological targeting of interleukin-1 receptor–associated kinase 4 (IRAK4) with inhibitor CA-4948 suppressed disease burden and inflammatory cytokines specifically in MPN without inducing toxicity in nondiseased models. These findings highlight vulnerabilities in MPN that are exploitable with emerging therapeutic approaches.