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Proline tRNA biogenesis as oncogenic drivers and therapeutic target in T cell acute lymphoblastic leukemia

Award Number: R37CA307194
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/08/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Proline tRNA biogenesis as oncogenic drivers and therapeutic target in T cell acute lymphoblastic leukemia - Proline tRNA biogenesis as oncogenic drivers and therapeutic target in T cell acute lymphoblastic leukemia Although transfer RNAs (tRNAs) have emerged as dynamic and significant regulators of cancer progression, a critical gap in knowledge still remains in defining the mechanisms linking tRNA deregulation to tumor pathogenesis and therapy resistance. The long-term goal is to define the role of tRNA deregulation in the biology of cancers with T cell acute lymphoblastic leukemia (T-ALL) as a disease model. Preliminary studies highlight that upregulated proline tRNA biogenesis contributes to T-ALL proliferation and viability. Specifically, expression of the bifunctional glutamyl-prolyl-tRNA synthetase (EPRS1) and tRNA-Pro isoacceptors (tRNAs with different anticodons but carry the same amino acid) is significantly upregulated in primary T-ALL samples relative to thymocytes and mature T cell subsets from healthy individuals. Pharmacological inhibiton of the prolyl tRNA synthetase (ProRS) activity of EPRS1, which aminoacylates proline tRNA isoacceptors with the cognate amino acid proline, induced cell death in T-ALL in vitro compared to T cells from healthy donors. Global proteomic analysis following ProRS inhibition identified singnificant decrease in the expression levels of proline rich oncogenic proteins, highlighting deregulated proline tRNA biogenesis as a critical adaptation in the establishment of oncogenic gene expression programs in T-ALL. The overall objectives in this application are (i) to determine the molecular mechanisms by which upregulated proline tRNA biogenesis promote oncogenic gene expression programs in T-ALL and (ii) determine the oncogenic role of this pathway in vivo. The rationale for this project is that mechanistic understanding of the role of proline tRNA biogenesis in T-ALL pathogenesis will provide a strong scientific framework to develop new cancer therapeutics targeting tRNA. The central hypothesis is that upregulated proline tRNA biogenesis is critical for initiation and progression of T-ALL. This central hypothesis will be tested using two specific aims: 1) Mechanistic dissection of the role of upregulated proline tRNA biogenesis in T-ALL and 2) Define the role EPRS1 in T-ALL initiation and progression using genetic murine models. In the first aim, proline tRNA biogenesis will be perturbed using orthogonal approaches in vitro (ProRS inhibition and CRISPRi silencing of tRNA-Pro genes) in cell line models and profiled using tRNA-Seq (RNA-seq), ribosome density profiling (Ribo-Seq) and total RNA-seq to identify changes in mRNA translation sensitive to proline tRNA expression and aminoacylation levels at single codon resolution. For the second aim, genetic murine models will be used to conditionally delete Eprs1 to test the effects of loss of Eprs1 in T-ALL initiation and progression. The research proposed in this application is innovative, because it explores previously overlooked roles of leukemic cell-intrinsic tRNA dysregulation in the development of T-ALL. Relapsed/refractory T-ALL with dismal prognosis remains a clinical urgency. The proposed research is significant because it paves the way for the development of novel cancer therapeutics focused on targeting tRNA regulatory pathways downstream of oncogenic activation in T-ALL and likely other cancers.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $473,372 )
2026	2026	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	4/9/2026	NEW	$473,372
														Subtotal = $473,372

Grand Total All Awards = $473,372

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Proline tRNA biogenesis as oncogenic drivers and therapeutic target in T cell acute lymphoblastic leukemia

Award Number: R37CA307194

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/08/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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