tRNAs have historically been viewed as adaptor molecules with the singular function of deciphering the genetic code during protein synthesis. Through expression profiling of tRNAs, we identified altered valine tRNA biogenesis to be an indicator of tumor-specific demand for amino acid valine for protein synthesis in T-cell acute lymphoblastic leukemia (T-ALL). Interestingly, exploiting this demand by reduction of dietary valine availability translated into reduced tumor growth and increased survival in preclinical models of T-ALL (Thandapani et al, Nature 2022). Our work, along with several recent reports, suggests understanding tRNA deregulation can reveal novel tumor specific dependencies in hematological malignancies (reviewed in Lee, Thandapani, Trends in Immunology, 2022).
Project I: Develop approaches to target valine tRNA biogenesis in T-ALL
As a paradigm of our overarching goal to develop approaches to target tRNA pathways, extending on our findings that valine tRNA biogenesis and valine bioavailability is critical for T-ALL survival, our lab is currently developing clinically translatable approaches to target valine tRNA biogenesis in T-ALL.
- Evaluate dietary valine restriction as a component of existing chemotherapies in T-ALL
- Identify synthetic lethal interactions with inhibition of valine tRNA biogenesis.
- Develop novel pharmacological inhibitors of valine tRNA biogenesis
Project II: To identify unique dependencies in tRNA biogenesis in acute leukemias
In this project, we want to extend our approach to other leukemia subtypes such as AML, MDS, B-ALL to extensively profile tRNA expression, modifications, aminoacylation status and couple it with functional genomic approaches to identify unique dependencies.
- To apply NGS and direct RNA sequencing approaches to profile tRNA expression, modifications and charging states in acute leukemia subtypes and normal hematopoietic subsets
- Functional genomic approaches (Cas9/Cas13d) to screen for tRNA pathway dependencies in acute Leukemia subtypes
- Deciphering the mechanisms governing pathologic tRNA functions in acute leukemias