Regulation of Skp2 by the Interleukin-7/STAT3 axis in T-cell acute lymphoblastic leukemia

• Grant number: 14/13546-4
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: August 22, 2014
• End date: December 21, 2014
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Aparecida Maria Fontes
• Grantee: Ricardo Bonfim Silva
• Supervisor: Nadia Carlesso
• Host Institution: Hemocentro de Ribeirão Preto. Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da USP (HCMRP). Secretaria da Saúde (São Paulo - Estado). Ribeirão Preto , SP, Brazil
• Institution abroad: Indiana University-Purdue University Indianapolis, United States
• Associated to the scholarship: 11/18664-7 - The role of lncRNA Evf-2 in the modulation of Hox genes and metastatic potential of Medulloblastoma, BP.DR

Abstract

SKP2 is the F-box protein of the E3 ubiquitin ligase complex that mediates target recognition and degradation of several cyclin-dependent kinase inhibitors as p27, p21 and p57, thus regulating cell cycle progression. Carlesso's group discovered that SKP2 is transcriptionally regulated by Notch signaling, and recently showed that SKP2 is overexpressed in pediatric T-cell acute lymphoblastic leukemia (T-ALL). Although activating mutations of Notch signaling are present in most T-ALL patients, it is unknown whether SKP2 plays a significant biological role in T-ALL. Cardoso's group showed that IL-7 downregulates the p27kip1 cell cycle inhibitor promoting cell cycle progression in T-ALL cells, and that IL-7-activated STAT3 signaling is required for T-cell leukemogenesis. The central hypotheses of this research project are that: i) oncogenic Notch signaling and the IL-7-triggered STAT3 signaling converge in the regulation of SKP2, to control leukemia cell proliferation and cell cycle progression; ii) SKP2 represents an effective molecular target in high-risk T-cell ALL and leukemia relapse; and, iii) SKP2 plays a critical role in the regulation and maintenance of leukemia-initiating cells in T-ALL. For this, will be performed defined experiments that will contribute to elucidate the precise contribution of the Notch and the IL-7/STAT3 circuitry to SKP2 regulation, and to the pre-clinical validation of SKP2 as a novel therapeutic target for high-risk and relapsed T-cell ALL. Also, these studies will contribute to define the potential role of SKP2 in the regulation of leukemia-initiating cells. (AU)