2025 Theses Doctoral
Genome-wide CRISPR screens for identification of therapeutic targets in hematological malignancies
Functional genomic screens using CRISPR technology have revolutionized the discovery of genetic vulnerabilities and synthetic lethal interactions in cancer, including hematological malignancies. Our work aims to contribute to existing knowledge on the molecular underpinnings governing response to targeted therapies in acute leukemia by leveraging the power of genome-wide CRISPR screens.
Specifically, we studied T cell acute lymphoblastic leukemia (T-ALL) and post-myeloproliferative neoplasm acute myeloid leukemia (post-MPN AML) which are aggressive hematological conditions with dismal prognosis in relapsed and advanced-age patients, respectively. Therapeutic targeting of NOTCH1 signaling in T-ALL using gamma secretase inhibitors (GSIs) and JAK/STAT signaling in post-MPN AML using Type I JAK2 inhibitors have shown promising results but were limited due to modest antileukemic activity and adverse side effects. Thus, finding synthetic lethal targets that could enhance the therapeutic activities of GSIs and JAK2 inhibitors are warranted.
Here, we performed genome-wide CRISPR screens to discover genes that show synergistic interactions with GSI and with JAK2 inhibitors. We present potential therapeutic targets to improve the antileukemic effects of GSI in T-ALL. In addition, we show that inhibition of the neddylation pathway circumvents GSI-induced gut toxicity by stabilizing HES1 protein. Lastly, we demonstrate that CREBBP/EP300 bromodomain inhibition potentiates JAK2 inhibition in post-MPN AML by downregulating oncogenic MYC and phosphorylated STATs levels and activity. Collectively, our findings corroborate the power of genome-wide CRISPR screens integrated with downstream functional and multi-omics analysis for the identification and characterization of potential therapeutic targets in hematological malignancies.
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This item is currently under embargo. It will be available starting 2026-01-03.
More About This Work
- Academic Units
- Biological Sciences
- Thesis Advisors
- Palomero, Teresa
- Ferrando, Adolfo
- Degree
- Ph.D., Columbia University
- Published Here
- January 15, 2025