Role of Inflammation in the Pathogenesis of Myeloproliferative Neoplasms

Rai, Shivam. Role of Inflammation in the Pathogenesis of Myeloproliferative Neoplasms. 2021, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: https://edoc.unibas.ch/90196/

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Myeloproliferative neoplasms (MPNs) are a group of diseases frequently caused by activating mutations in JAK2, CALR or MPL and characterized by aberrant proliferation of the erythroid, megakaryocytic and myeloid lineages. They represent clonal disorders of the hematopoietic stem cell (HSC) with an inherent tendency towards leukemic transformation. MPNs are subdivided into three disease entities: polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). JAK2-V617F is the most frequently recurring somatic mutation in MPN patients, but it can also be found in healthy individuals with clonal hematopoiesis of indeterminate potential (CHIP) with a frequency much higher than the incidence of MPN. This suggests that the acquisition of the JAK2-V617F is not the rate-limiting step and other factors might be required for the expansion of the JAK2 mutated clone and initiation of MPN disease. MPN is often linked with a chronic inflammatory state due to elevated production of inflammatory cytokines and chemokines from hematopoietic and non-hematopoietic cells. Interleukin-1β (IL-1β) is one of the master regulators of the inflammatory state and its aberrant activity has been implicated in various pathological diseases including MPN. In the first part of this study, we focused on the early stages of MPN disease initiation and examined the role of IL-1β in this context. Our results showed that IL-1β secreted from mutant cells promoted the expansion of JAK2-V617F clones and loss of IL-1β from mutant cells resulted in reduced frequency of MPN disease initiation. Furthermore, our results indicated that IL-1β was required for optimal stem cell function and long-term repopulation capacity of JAK2-V617F HSCs. Moreover, we showed that early secretion of IL-1β from mutant cells caused neuronal damage in the bone marrow resulting in loss of nestin-positive stromal cells. Loss of nestin-positive stromal cells favored clonal expansion and MPN disease manifestation. In the second part of the study, we showed that JAK2-V617F mutation correlated with increased IL-1 signaling in MPN patients. We showed that genetic deletion of IL-1β from mutant cells resulted in reduced production of inflammatory cytokines, reduced MPN symptom burden and myelofibrosis. Notably, pharmacological inhibition of IL-1β or NLRP3 inflammasome complex reduced myelofibrosis. Combined targeting of IL-1β with JAK1/2 inhibitor, ruxolitinib resulted in complete reversal of myelofibrosis, reduced production of inflammatory cytokines and normalization of MPN constitutional symptoms in vivo. Overall, our results showed that IL-1β is required for optimal MPN disease initiation and progression to myelofibrosis.
Advisors:Skoda, Radek C. and Handschin, Christoph and Fehling, Hans Joerg
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Hämatologie > Molekulare Medizin (Skoda)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Hämatologie > Molekulare Medizin (Skoda)
UniBasel Contributors:Skoda, Radek C. and Handschin, Christoph
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:14873
Thesis status:Complete
Number of Pages:165
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss148732
edoc DOI:
Last Modified:06 Dec 2022 05:30
Deposited On:05 Dec 2022 10:14

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