A Combination Of Il7r Alpha And Nras Mutations Up-Regulates Bcl-2 And Cmyc Levels Leading To Formation Of T-Cell Acute Lymphoblastic Leukemia.

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive leukemia derived from T-cell precursors. With current treatments, survival rate is high, but the treatments are highly toxic with severe side effects. In addition, relapse is relatively common in T-ALL and is exceptionally difficult to salvage with hematopoietic stem cell transplant which is essentially the only treatment. Thus, a better understanding of T-ALL etiology and subtypes is required to develop the warranted improved therapies. Individual mutations in IL7Rα and RAS pathways have been previously shown to be prevalent in T-ALL and especially in relapsed patients. However, it is not fully understood how these mutations are involved in disease origin and progression. In addition, we have previously shown that mutations in either IL7Rα or NRAS alone are not sufficient to induce T-ALL. Nevertheless, a combination of both causes severe T-ALL in mice which can be ameliorated by IL7Rα and NRAS signaling inhibition. To better understand how this combination can be utilized to understand disease etiology, we have tested for combinations of mutations that resulted in varying expression levels of the mutated proteins. Our results revealed that a specific ratio between IL7Rα and NRAS expression is necessary to generate T-ALL in mice. Transplanting transduced lymphocyte progenitors into RAG-/- immune-deficient mice allowed us to find an optimal order of the two oncogenes in a polycistronic vector that leads to severe T-ALL. A comparison of transplants from several arrangements of oncogenes in the vector enabled us to screen for potential regulatory pathways that are important for disease progression in vivo by analyzing the cancer cells' transcriptome and proteome. We found that the disease is characterized by a significant increase in IL7Rα-mediated BCL-2 expression, and an increase in c-Myc protein levels, via NRAS signaling. Our results are confirmed by induction of a similar phenotype with a combination of overexpressed WT c-Myc and mutant IL7Rα, which caused severe leukemia as early as 16 days post-transplant. Taken together, we developed a robust model to study T-ALL in mice, shed light on novel pathways of oncogenesis and discovered new targets for intervention that could lead to better therapeutic development. Citation Format: Hila Winer, Gisele Rodrigues, Wenqing Li, Julie Hixon, Scott K. Durum. A combination of IL7Rα and NRAS mutations up-regulates Bcl-2 and cMyc levels leading to formation of T-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2462.