Characterizing the impact of inflammatory signaling on MPN disease persistence

• Applicant: Professor Dr. Philipp Jost
• Subject Area: Hematology, Oncology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 517204983

Resistance to programmed cell death is a hallmark of cancer, which secures the survival of cells during oncogenic transformation and often results in therapy resistance. The inflammatory phenotype observed in MPN patients is a critical downstream event in JAK2-mutated MPN pathophysiology (Kleppe et al. 2015; Fleischman et al. 2011; Pronk et al. 2011; Koschmieder et al. 2016). However, it remains elusive which additional inflammatory pathway contribute to MPN disease progression and persistence. Regulated necrosis (necroptosis) governed by receptor-interacting protein kinase (RIPK) 1 and RIPK3 critically controls myeloid cell integrity, inflammation and acute myeloid neoplasia (Yabal et al. 2014; Höckendorf et al. 2016; Jost and Höckendorf 2019). Published data and our preliminary results show that MPN patients present with elevated levels of proinflammatory cytokines as well as with increased expression of the necroptosis mediator RIPK3 (Dill et al. 2023). These data support a direct involvement of necroptotic signaling in MPN disease progression and argue that inflammation-driven proliferation/survival of MPN cells impact on disease pathophysiology. Hence, this proposal sets out to elucidate how necroptosis contributes to MPN by dissecting its inflammatory signaling output in comparison to its capability for programmed cell death induction. This proposal will elucidate the role of necroptosis-induced inflammation on JAK2V617F-mutated MPN cells by testing cellular differentiation, survival and proliferation of JAK2V617F-mutated myeloid cells with or without perturbed necroptotic signaling. This will be performed using Jak2V617F/+ vav-Cre+ Ripk3-/- BM mononuclear cells from mice. In addition, we will study the molecular contribution of prolonged cell survival to MPN in vivo using Jak2V617F/+ vav-Cre+ mice with or without RIPK3 expression in vivo over the course of disease. And lastly, we will target MPN persistence by pharmacologic inhibition of JAK2 signaling, RIPK3 signaling or both in vivo using pharmacologic inhibitors and co-deletion of the necroptosis executor Mixed lineage kinase domain-like protein (MLKL). In summary, this proposal will dissect the contribution of necroptosis-induced inflammation and cell death on MPN pathophysiology. We anticipate that targeting necroptosis-associated signaling effectively suppresses the MPN stem cell compartment by inhibiting inflammation-mediated disease progression and thereby block MPN activity and persistence. Moreover, we expect that combined inhibition of JAK2 and RIPK3 significantly potentiates the repression of malignant MPNs and improves the long-term survival of MPN mice thereby providing the basis for future clinical translation.

• DFG Programme: Research Units
• Subproject of: FOR 5659: TARGET-MPN: TARgetinG disease pErsisTence and progression of MyeloProliferative Neoplasms (MPN)
• International Connection: Austria
• Partner Organisation: Fonds zur Förderung der wissenschaftlichen Forschung (FWF)