Abstract

Myeloid malignancies are a group of heterogenous and clonal disorders that include myeloproliferative neoplasms (MPNs) and acute myeloid leukemia (AML). These blood cancers are driven by characteristic oncogenes and propagated by pro-inflammatory niches; MPNs demonstrate hyperactive JAK-STAT signaling and upregulate cytokines including TNF, IL-6, and IL-8. Current therapeutics such as ruxolitinib targeting JAK2 providing symptomatic benefit to MPN patients but are not curative and do not prevent disease transformation to acute myeloid leukemia (AML). As such, greater understanding of the underlying disease biology is still required with means of uncover cancer dependencies. Here, we utilize a series of multi-omic approaches to evaluate novel therapeutics strategies for myeloid malignancies. First, we perform comprehensive profiling of current JAK inhibitors (ruxolitinib, fedratinib, momelotinib, and pacritinib) that are FDA-approved or undergoing phase III clinical trials for MPN patients to help guide the use of specific inhibitors in personalized therapy. Next, we assessed targeting NFκB signaling, another pathway elevated in MPN, via inhibitor pevonedistat as a therapeutic modality for myelofibrosis. Lastly, we uncover a novel DUSP6-RSK1-S6 axis important for MPN disease transformation and RSK1 as a core dependency in myeloid malignancies. Using small molecules including RSK inhibitor PMD-026, currently under evaluation in phase I/Ib clinical trials for breast cancer patients, we demonstrate therapeutic efficacy across a plethora of syngeneic and patient-derived xenograft mouse models of MPN and AML. Together, these efforts establish multiple novel and promising therapeutic strategies for the treatment of myeloid malignancies.

Committee Chair

Stephen Oh

Committee Members

Barbara Warner; Clay Semenkovich; Daniel Goldberg; Marco Colonna; Michael Province

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology and Biomedical Sciences

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

4-17-2025

Language

English (en)

Author's ORCID

https://orcid.org/0009-0005-1905-3166

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