Investigation of cooperative oncogenes in IL7R-mediated acute lymphoblastic leukemia emergence

• Grant number: 16/20071-8
• Support type: Scholarships in Brazil - Master
• Effective date (Start): November 01, 2016
• Effective date (End): October 31, 2018
• Field of knowledge: Biological Sciences - Biochemistry
• Principal Investigator: Leticia Fröhlich Archangelo
• Grantee: Tiago Selau Rodrigues
• Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 14/01458-3 - Defining the functional role of the splicing factor regulator (KIS) during leukemogenesis using a murine bone marrow transplantion model, AP.JP

Abstract

Among different types of hematological cancer, acute lymphoblastic leukemia (ALL) is characterized by lymphoid progenitor cells bearing inherited genetic mutations and/or accumulated epigenetic alterations, affecting both T- and B-cell lineages, mainly during childhood. Genomic profiling has improved our understanding of the several pathways altered in ALL cells, and brought the cure rates to better parameters. Interleukin-7 (IL-7) is a cytokine required for normal development of lymphoid cells, and promote anti-apoptotic and proliferative responses by binding to interleukin-7 receptors (IL-7R). Overstimulation of IL-7R signalling may provoke leukemogenesis. A gain-of-function mutation on IL7R gene, found in 9% of T-ALL studied cases, was characterized by resulting in the formation of IL-7R± homodimers through disulphide-bonds of unnatural cysteine residues, which cause a constitutive activation of IL-7R signalling. However, the transformation to a full leukemic state may require additional mechanisms that cooperate to this mutation. Hence the present study aims to identify cooperative oncogenes and characterize their role in ALL emergence. For this purpose, Ba/F3 cells carrying wild and mutated versions of IL7R will be transduced with a lentivirus-mediated shRNA library, cultivated and verified for the presence of potential oncogenes contributing to the IL7R mutation. The expected outcome may improve the understanding of leukemogenic mechanisms and identification of potential molecular targets for therapy development.