Targeting Proline Trna Biogenesis for Treatment of T Cell Acute

T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive blood cancer marked by the abnormal growth of immature thymocytes. While the survival rate in pediatric cases is around 80%, there remains a significant 20% of patients who succumb to the disease due to relapse or resistance to treatment. Moreover, adult survival rates are below 50% due to higher treatment-related toxicities. This highlights the critical need for new therapeutic approaches. At the molecular level, constitutive NOTCH1 signaling, resulting from activating mutations in NOTCH1 gene observed in over 60% of patients, is a major driver of the disease. In our recent work, we had identified an extensive oncogenic NOTCH1 dependent rewiring of global tRNA biogenesis in T-ALL and demonstrated that tRNA deregulation are critical contributors to the disease pathogenesis of T-ALL. In further underlining tRNA pathway as novel therapeutic targets in T-ALL, we report pharmacological inhibition of prolyl-tRNA synthetase (ProRS) domain, that charges proline tRNAs with the cognate proline amino acid, to decrease proliferation and induces cell death in pre-clinical models of T-ALL. Expression of the bifunctionl glutamyl-prolyl-tRNA synthetase (EPRS1) and proline tRNAs is significantly upregulated in primary T-ALL samples relative to thymocytes from healthy individuals. Moreover, CRISPR knockdown of EPRS1 and proline tRNAs in T-ALL cell lines leads to reduced cell fitness, underscoring the critical role of this pathway in tumor proliferation and survival. NCP26 is a new pyrazinamide-based drug that targets the ProRS domain of EPRS1 and its efficacy in treating multiple myeloma was thoroughly evaluated in a recent study. We show that NCP26 effectively inhibits proliferation and enhances apoptosis in T-ALL cell lines and PDX samples. In contrast, T cells from healthy donors show no signs of apoptosis and exhibit only minimal proliferation inhibition, confirming the lack of toxicity on normal T cells. Our findings identify upregulated proline tRNA biogenesis as a critical adaptation in T-ALL pathogenesis and provide a molecular basis to target ProRS in T-ALL.

Payne:CoraFluor: Patents & Royalties. Mazitschek:CoraFluor: Patents & Royalties.