Palaniraja Thandapani, Ph.D.

Targeting tRNA deregulation in hematological malignancies

Mechanisms regulating mRNA translation account for ~40% of gene expression changes. Protein synthesis is also a major consumer of energy and amino acids in proliferating cells. Tumor growth, microenvironment and metabolic adaptation can restrict availability of certain amino acids for protein synthesis, resulting in novel dependencies that can be targeted by either dietary or pharmacalogical intervention. Using a combination of tRNA expression profiling and functional genomic screens targeting genes involved in tRNA biogenesis, we had identified altered tRNA biogenesis as an indicator of tumor specific amino acid demand for protein synthesis in T-cell acute lymphoblastic leukemia (T-ALL). Moreover, exploiting this demand by dietary restriction of the target amino acid translated into reduced tumor growth and increased survival in preclinical models of T-ALL. These results have revealed that understanding deregulation of tRNA biogenesis pathways can reveal novel targetable dependencies in tumors.

tRNAs have been largely overlooked as mere adaptor molecules for protein synthesis. However, recent studies along with our own work suggest dynamic regulation of tRNA transcription and biogenesis in cancer to support a specific oncogenic program. The long-term research goals of our lab are to define the role of tRNA deregulation in the biology of cancers employing genome wide approaches to profile tRNA expression and epitranscriptomic changes and integrate this information with functional CRISPR screens, mechanistic studies and novel approaches (dietary, RNA therapeutics, synthetic lethality) to identify and target altered tRNA biogenesis in hematological malignancies.

Degree-Granting Education

Postgraduate Training