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PhD thesis-Pu Zhang-Final-20211224.pdf (6.55 MB)

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Exploration of synergistic interactions of oncogenic signals or concurrent driver mutations as novel therapeutic targets to treat AML

Zhang, Pu
http://rave.ohiolink.edu/etdc/view?acc_num=osu1639883708143069

Abstract Details

2022, Doctor of Philosophy, Ohio State University, Pharmaceutical Sciences.
Acute myeloid leukemia (AML) is one of the most lethal forms of hematologic malignancies with low survival rates (<8%) in patients older than 60. With FDA-approved targeted therapies and immunotherapies and advancement of sequencing techniques, the treatment strategies for AML has undergone a paradigm shift in the last decade. But because of inter- and intra-patient heterogeneity, identification of a therapy that can broadly target different subtypes of AML is very challenging. Two mutations and/or concurrent signaling abnormalities are needed to synergistically license leukemia initiation and maintenance. NAMPT is a rate-limiting NAD+ generation enzyme, involving in various functions of leukemia cells. Upon discovery of the roles of NAMPT in metabolic reprograming, small inhibitors that target NAMPT have been soon developed. In our published studies, we showed that NAMPT inhibitor, KPT-9274, was able to induce potent cytotoxicity of AML patient cells and provided survival benefit for murine models of disseminated AML. NAMPT inhibition can selectively eliminate leukemia stem cell population. Although NAMPT inhibitors demonstrated exciting preclinical properties, dose-limiting toxicities including thrombocytopenia and gastrointestinal toxicities were observed. KPT-9274 exhibited gender-dependent toxicity in kidney and anemia, highlighting the necessity of identification of synthetic lethal partners for KPT-9274 treatment. By using CRISPR screen, we were able to identify histone acetylases, HDAC8 and SIRT6, as co-essential genes with KPT-9274 treatment. HDAC8 or SIRT6 inhibition sensitized AML cell lines and primary patient cells to NAMPT inhibition. Importantly, a pan-HDAC inhibitor, AR-42, eliminated leukemia initiating cells (LICs) in vitro and in vivo in combination with KPT-9274 by altering transcriptional patterns of LICs and shutting down multiple DNA repair pathways. Understanding of cooperativity of co-mutations in driving leukemogenesis offers another means of identifying druggable targets to prevent leukemia transformation. TP53 and TET2 co-mutations are present in a subset of AML patients who have a very poor prognosis. To study the mechanism of TP53/TET2 co-mutation-driven leukemia, we developed an elegant murine model which yielded essential insights into the complex nature of acute leukemia transformation. TP53-/-TET2-/- mice developed multi-lineage leukemia which can be skewed towards AML upon TLR simulation. TP53-/- and TET2-/- transformed and conferred self-renewal properties to GMP progenitors. TP53 and TET2 co-mutation with AML phenotype altered transcriptomes of myeloid progenitors and upregulated deubiquitinase A20 levels and ERK/MEK and IL-6-JAK-STAT3 signaling. In addition, scRNA-seq revealed a distinct blast-like population with enhanced migratory properties and exhaustive T cells (CD3e+TIGIT+LAG3+PD1+) in TP53-/-TET2-/-AML tumor microenvironment. Collectively, these data provide evidence that our CRISPR screen and TP53/TET2 co-mutation studies may have exploited key vulnerabilities of the acute myeloid cells which can be translated this into clinical benefit.
Rosa Lapalombella (Advisor)
John Byrd (Committee Member)
Sharyn Baker (Committee Member)
Moray Campbell (Committee Member)
133 p.
Bioinformatics; Cellular Biology; Molecular Biology; Pharmaceuticals; Pharmacology; Pharmacy Sciences
AML, NAMPT, TP53, TET2, HDAC8, SIRT6, DNA damage, CRISPR screen, RNA-seq, scRNA-seq, leukemia, toxicity

Recommended Citations

Citations

  • Zhang, P. (2022). Exploration of synergistic interactions of oncogenic signals or concurrent driver mutations as novel therapeutic targets to treat AML [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1639883708143069

    APA Style (7th edition)

  • Zhang, Pu. Exploration of synergistic interactions of oncogenic signals or concurrent driver mutations as novel therapeutic targets to treat AML. 2022. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1639883708143069.

    MLA Style (8th edition)

  • Zhang, Pu. "Exploration of synergistic interactions of oncogenic signals or concurrent driver mutations as novel therapeutic targets to treat AML." Doctoral dissertation, Ohio State University, 2022. http://rave.ohiolink.edu/etdc/view?acc_num=osu1639883708143069

    Chicago Manual of Style (17th edition)

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This open access ETD is published by The Ohio State University and OhioLINK.
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