In vivo ablation of NFκB 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 patient-derived xenograft models of myelofibrosis.

Hyperactivation of the NFκB cascade propagates oncogenic signaling and pro-inflammation, which together augments disease burden in myeloproliferative neoplasms (MPNs). Here, we systematically ablate NFκB 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 Jak2V617F and MPLW515L-driven onset of polycythemia vera and myelofibrosis disease hallmarks, respectively. In PDXs, RELA-knockout diminished leukemic engraftment and bone marrow fibrosis while extending survival. Knock-out of upstream effector Myd88 also alleviated disease burden; conversely, perturbation of negative regulator miR-146a microRNA induced earlier lethality and exacerbated disease. Perturbation of NFκB 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 non-diseased models. These findings highlight vulnerabilities in MPN that are exploitable with emerging therapeutic approaches.