Graduation Year

2023

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Biology (Cell Biology, Microbiology, Molecular Biology)

Major Professor

Eric Padron, M.D.

Committee Member

Conor C. Lynch, Ph.D.

Committee Member

Keiran S. Smalley, Ph.D.

Committee Member

Stephen Oh, M.D., Ph.D.

Keywords

Biogenesis, GM-CSF, PDX

Abstract

Chronic Myelomonocytic Leukemia (CMML) is a rare myeloid malignancy with a dismal prognosis and no therapeutic options which are capable of altering the natural course of the disease. There remains a significant need for novel therapies that are able to meaningfully improve patient outcomes. In this study we explore the effectiveness of Bromodomain and Extra-Terminal domain protein inhibitor (BETi) combinations in CMML. Preclinical studies in myeloid neoplasms have demonstrated efficacy of BETi. However, BETi demonstrate poor single agent activity in clinical trials. Several studies suggest that combinations with other anti-cancer inhibitors may enhance the efficacy of BETi. To nominate BETi combination therapies for myeloid neoplasms, we used a chemical screen with therapies currently in clinical cancer development and validated this screen using a panel of myeloid cell lines, heterotopic cell line models, and PDX models of disease. We identified PIM inhibitors (PIMi) as therapeutically synergistic with BETi in myeloid leukemia models and show that PIM inhibition is able to overcome both single agent BETi and dual BETi/JAKi persistence. Mechanistically, we show that PIM kinase is increased after BETi treatment, and that PIM kinase upregulation is sufficient to induce persistence to BETi and sensitize cells to PIMi. Further, we demonstrate that miR-33a downregulation is the underlying mechanism driving PIM1 upregulation and its downregulation is likely due to global BETi dependent impairments in miRNA biogenesis. We also show that GM-CSF hypersensitivity, a hallmark of CMML, represents a molecular signature for sensitivity to combination therapy. Inhibition of PIM kinases is a potential novel strategy for overcoming BETi persistence in myeloid neoplasms. Our data supports further clinical investigation of this combination.

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