Abstract B57: A combination of IL7Rα and NRAS mutations sheds light on the oncogenesis of T-cell acute lymphoblastic leukemia in a murine model

Abstract Acute lymphoblastic leukemia (ALL) is the most common cancer in children. While most cases of ALL arise from B-cell precursors, 15% originate from T cells in the thymus (T-ALL). With current treatments, survival rate is high, but relapse occurs in 15-20% of children. In addition, most treatments are highly toxic, with severe side effects. Approximately 10% of T-ALL patients have somatic gain-of-function mutations in IL7Rα gene, and 15-22% of ALL patients have mutations in NRAS or KRAS. Furthermore, Ras pathway mutations are responsible for 30%-50% of ALL relapse. Recently, our lab showed that mutations in human IL7Rα alone (c.731_732insTTGTCCCAC) or human NRAS alone (G13D) are not sufficient to induce T-ALL from primary cells. However, a combination of both causes severe T-ALL in mice. Treatment with inhibitors against IL7Rα and NRAS signaling led to prolonged survival in these mice. Our new data indicate that the correct ratio between IL7Rα and NRAS expression is necessary to generate T-ALL in mice. Using RAG-/- mice injected with primary thymocytes transduced with mutated IL7Rα and NRAS in the optimal sequence in a polycistronic vector led to fatal disease 3 weeks after injection. These mice showed a 30-fold increase of leukocytes in the blood, spleen, and thymus, 80-fold increase in the lymph nodes, and a 5-fold increase in spleen weight, all indications of severe T-ALL. There was no indication of disease progression in mice injected with either empty vector or wild-type IL7Rα and mutated NRAS. To identify the pathways involved in T-ALL by these mutations, we used mass spectrometry and RNA sequencing. Our analysis showed significant increases in the well-known antiapoptotic, B-cell lymphoma 2 (BCL-2), mRNA, and protein levels and a major decrease in the proapoptotic BCL-2 antagonist/killer 1 (BAK-1) protein levels. In this manner, combination of both IL7Rα and NRAS mutations resulted in high Bcl-2:Bak-1 ratio, supported also by Western blot analysis. In addition, we observed a significant increase in the protein cytokinesis midbody regulator citron kinase (Cit), potentially leading to increased thymocytes proliferation and driving T-ALL formation. Taken together, our lab developed a strong model to study T-ALL in mice, shedding light on novel pathways of oncogenesis and targets for better therapeutic development. Citation Format: Hila Winer, Gisele Rodrigues, Wenqing Li, Julie Hixon, Scott Durum. A combination of IL7Rα and NRAS mutations sheds light on the oncogenesis of T-cell acute lymphoblastic leukemia in a murine model [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B57.

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