Investigation of ubiquitin-ligase HUWE1 in the modulation of RAS pathway in leukemia models

• Grant number: 15/12146-5
• Support Opportunities: Scholarships in Brazil - Master
• Start date: December 01, 2015
• End date: September 30, 2017
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Vanessa da Silva Silveira
• Grantee: Mariana Tannús Ruckert
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

In the last few years acute lymphoblastic leukemia (ALL) patients prognosis have been significantly improved, however, some subgroups, such as Ph positive leukemia frequently experience relapse and low cure rates, representing a challenge. The Ph positive leukemias show the BCR-ABL fusion gene, that arises from a translocation between chromosomes 9 and 22. This mutation gives rise to the tyrosine-kinase BCR-ABL, responsible for the hyperactivation of RAS pathway which, among other functions, regulates the oxidative stress levels that are necessary for neoplastic cells' survival. Results previously obtained by Silveira et al. (2013) have shown surprising and interesting data that suggests an association between hyperactivation of RAS pathway and a favorable treatment outcome, pointing to a new research approach. Besides this one, other reports have also shown signs that the hyperactivation of RAS pathway may be related to the increase of cell death. Even though the current approach for Ph positive leukemia's treatment is the use of tyrosine-kinase inhibitors, a lot of patients develop complex resistance mechanisms and relapse. Considering the aforementioned information, this project suggests that constitutive hyperactivation of RAS pathway (promoted by the activity of tyrosine-kinase BCR-ABL), increased by the loss of negative feedback mechanisms can lead to a metabolic imbalance and expose tumor cells to a state of oxidative stress that is higher than the tolerated threshold, thus being highly toxic. In this case, the level of toxicity to which the cell is exposed can sensitize it to chemotherapy. The elucidation of these mechanisms is of great importance and can enable the discovery of new therapeutic targets, providing alternative strategies to the treatment of high risk patients and those that develop resistance to chemotherapy.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

RUCKERT, MARIANA TANNUS; BROUWERS-VOS, ANNET Z.; NAGANO, LUIS FERNANDO P.; SCHURINGA, JAN JACOB; SILVEIRA, VANESSA SILVA. HUWE1 cooperates with RAS activation to control leukemia cell proliferation and human hematopoietic stem cells differentiation fate. Cancer Gene Therapy, v. 27, n. 10-11, JUL 2020. (15/10694-5, 15/12146-5)

RUCKERT, M.; BROUWERS-VOS, A.; GONZAGA, L. G.; SCHURINGA, J. J.; SILVEIRA, V. S.. Impacts of HUWE1 Knockdown in Human Hematopoietic Stem Cells with A KRAS (G12V) Mutation. PEDIATRIC BLOOD & CANCER, v. 64, p. 2-pg., 2017-11-01. (15/12146-5)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

RUCKERT, Mariana Tannús. Investigation of ubiquitin-ligase HUWE1 in the modulation of RAS pathway in leukemia models. 2017. Master's Dissertation - Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) Ribeirão Preto.