Evaluation of TP53/TP73 pathway in engraftment of acute promyelocytic leukemia cells in xenotransplantation model

• Grant number: 17/23117-1
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: March 01, 2018
• End date: March 31, 2022
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Eduardo Magalhães Rego
• Grantee: Diego Antonio Pereira Martins
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated scholarship(s): 19/14057-0 - Evaluation of the TP53/TP73 pathway in the engraftment of primary acute promyelocytic leukemia cells using a xenotransplantation model, BE.EP.DR

Abstract

Current models of xenotransplantation engines used as in vivo study models of human leukemic processes have failed to reconstruct disease-related pathophysiological processes due to non-similarity to the human marrow niche. To describe, the evaluation of the high-renewal processes, differentiation and transformation of human hematopoietic stem cells (HSCs) and leukemia (LSCs), as well as their evaluation as to the efficacy of new treatment modalities, should be performed in species-specific. This is supported by the fact that some leukemic subtypes, such as human promyelocytic leukemia (APL). Acute leukemias, these subtypes are still subject to high mortality rates and risk of relapse. In this sense, it is believed that genetic variations that confer greater resistance to the leukemic clone can influence the capacity of grafting, and its evaluation in vivo. Previous studies in our group have shown that a higher expression ratio ”Np73 / TAp73 is associated with a worse prognosis in LPA (lower overall survival and disease-free survival) and resistance to cytarabine-induced apoptosis. ”Np73, a truncated form of the TP73 gene, acts as a potent inhibitor of the transcriptional activity of TP53 and TAp73 proteins, thus playing an important role in cell proliferation and death. Thus, an oncogenic activity of the TP73 gene is determined by the balance between it's transcriptionally active (TAp73) and inactive isoforms (”Np73), and this relationship correlates with clinical prognosis and treatment failure in several human malignancies. Thus, the present work aims to determine how the TP53 / TP73 pathway is associated with a greater capacity of grafting in induced CD34 + cells and of patients with APL in humanized xenotransplantation models. Underlying, we will investigate the mechanisms by which the TP53 / TP73 pathway can confer PML-RARa + cells advantages of grafting, such as changes in proliferation, viability, cell cycle, apoptosis and clonogenic capacity. In addition, evaluations or transcriptome of patients with APL who obtained and who failed to graft in xenotransplantation models, in order to identify possible targets for TP53 / TP73 regulation. Expression of TP53 / T73 pathway targets will be investigated by real-time PCR and Western blot.

Scientific publications

(16)

(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)

WEINHAUSER, ISABEL; PEREIRA-MARTINS, DIEGO A.; ORTIZ, CESAR; SILVEIRA, DOUGLAS R.; SIMOES, LUISE A. A.; BIANCO, THIAGO M.; ARAUJO, CLEIDE L.; KOURY, LUISA C.; MELO, RAUL A. M.; BITTENCOURT, ROSANE I.; et al. Reduced SLIT2 is Associated with Increased Cell Proliferation and Arsenic Trioxide Resistance in Acute Promyelocytic Leukemia. CANCERS, v. 12, n. 11, NOV 2020. (17/23117-1, 13/08135-2, 15/09228-0)

VICARI, HUGO PASSOS; COELHO-SILVA, JUAN LUIZ; PEREIRA-MARTINS, DIEGO A.; LUCENA-ARAUJO, ANTONIO ROBERTO; LIMA, KELI; LIPRERI DA SILVA, JEAN CARLOS; SCHEUCHER, PRISCILA SANTOS; KOURY, LUISA C.; DE MELO, RAUL A.; BITTENCOURT, ROSANE; et al. STMN1 is highly expressed and contributes to clonogenicity in acute promyelocytic leukemia cells. INVESTIGATIONAL NEW DRUGS, NOV 2021. (19/01700-2, 20/12842-0, 17/23117-1, 19/23864-7, 17/24993-0)

THOME, CAROLINA HASSIBE; FERREIRA, GERMANO AGUIAR; PEREIRA-MARTINS, DIEGO ANTONIO; DOS SANTOS, GUILHERME AUGUSTO; ORTIZ, CESAR ALEXANDER; BOTELHO DE SOUZA, LUCAS EDUARDO; SOBRAL, LAYS MARTINS; ARAUJO SILVA, CLEIDE LUCIA; SCHEUCHER, PRISCILA SANTOS; GIL, CRISTIANE DAMAS; et al. NTAL is associated with treatment outcome, cell proliferation and differentiation in acute promyelocytic leukemia. SCIENTIFIC REPORTS, v. 10, n. 1, JUN 25 2020. (13/07675-3, 13/08135-2, 16/03809-3, 17/23117-1)

SILVEIRA, DOUGLAS R. A.; COELHO-SILVA, JUAN L.; SILVA, WELLINGTON F.; VALLANCE, GRANT; PEREIRA-MARTINS, DIEGO A.; MADEIRA, MARIA I. A.; FIGUEREDO-PONTES, LORENA L.; VELLOSO, ELVIRA D. R. P.; SIMOES, BELINDA P.; PENIKET, ANDY; et al. A multicenter comparative acute myeloid leukemia study: can we explain the differences in the outcomes in resource-constrained settings?. Leukemia & Lymphoma, v. 62, n. 1, p. 147-157, JAN 2 2021. (16/23191-4, 17/23117-1)

LIMA, KELI; PEREIRA-MARTINS, DIEGO ANTONIO; LINS DE MIRANDA, LIVIA BASSANI; COELHO-SILVA, JUAN LUIZ; LEANDRO, GIOVANA DA SILVA; WEINHAUSER, ISABEL; CAVAGLIERI, RITA DE CASSIA; LEAL, ALINE DE MEDEIROS; DA SILVA, WELLINGTON FERNANDES; ALENCAR DE LIMA LANGE, ANA PAULA; et al. The PIP4K2 inhibitor THZ-P1-2 exhibits antileukemia activity by disruption of mitochondrial homeostasis and autophagy. BLOOD CANCER JOURNAL, v. 12, n. 11, p. 11-pg., 2022-11-09. (15/09228-0, 20/12842-0, 19/23864-7, 21/11606-3, 17/23117-1)

ERDEM, AYSEGUL; MARIN, SILVIA; PEREIRA-MARTINS, DIEGO A.; GEUGIEN, MARJAN; CUNNINGHAM, ALAN; PRUIS, MAURIEN G.; WEINHAUSER, ISABEL; GERDING, ALBERT; BAKKER, BARBARA M.; WIERENGA, ALBERTUS T. J.; et al. Inhibition of the succinyl dehydrogenase complex in acute myeloid leukemia leads to a lactate-fuelled respiratory metabolic vulnerability. NATURE COMMUNICATIONS, v. 13, n. 1, p. 15-pg., 2022-04-19. (17/23117-1)

PEREIRA-MARTINS, DIEGO A.; WEINHAUSER, ISABEL; COELHO-SILVA, JUAN LUIZ; FRANCA-NETO, PEDRO L.; ALMEIDA, LUCIANA Y.; BIANCO, THIAGO M.; SILVA, CLEIDE L.; FRANCA, RAFAEL F.; TRAINA, FABIOLA; REGO, EDUARDO M.; et al. MLL5 improves ATRA driven differentiation and promotes xenotransplant engraftment in acute promyelocytic leukemia model. CELL DEATH & DISEASE, v. 12, n. 4, APR 6 2021. (16/23191-4, 17/23117-1, 13/08135-2, 15/09228-0)

COELHO-SILVA, JUAN L.; SILVEIRA, DOUGLAS R. A.; PEREIRA-MARTINS, DIEGO A.; ROJAS, CESAR A. O.; LUCENA-ARAUJO, ANTONIO R.; REGO, EDUARDO M.; MACHADO-NETO, JOAO A.; BENDIT, ISRAEL; ROCHA, VANDERSON; TRAINA, FABIOLA. Molecular-Based Score inspired on metabolic signature improves prognostic stratification for myelodysplastic syndrome. SCIENTIFIC REPORTS, v. 11, n. 1, JAN 18 2021. (14/50947-7, 17/23117-1, 13/08135-2, 16/23191-4, 17/19864-6)

DE ALMEIDA, LUCIANA YAMAMOTO; PEREIRA-MARTINS, DIEGO A.; WEINHAEUSER, ISABEL; ORTIZ, CESAR; CANDIDO, LARISSA A.; LANGE, ANA PAULA; DE ABREU, NAYARA F.; MENDONZA, SILVIA E. S.; DE DEUS WAGATSUMA, VIRGINIA M.; DO NASCIMENTO, MARIANE C.; et al. The Combination of Gefitinib With ATRA and ATO Induces Myeloid Differentiation in Acute Promyelocytic Leukemia Resistant Cells. FRONTIERS IN ONCOLOGY, v. 11, SEP 28 2021. (17/00775-3, 16/17521-1, 10/16966-3, 15/09228-0, 17/23117-1, 13/08135-2, 13/11817-8, 11/18313-0, 11/17111-4, 16/02713-2, 17/08430-5)

DE ALMEIDA, LUCIANA YAMAMOTO; PEREIRA-MARTINS, DIEGO ANTONIO; GOUVEA LIMA, ANA SILVIA; BAGGIO, MARCIA SUELI; DE ARAUJO KOURY, LUISA CORREA; LANGE, ANA PAULA; BASSI, SARAH CRISTINA; SCHEUCHER, PRISCILA SANTOS; REGO, EDUARDO MAGALHAES. Interleukin-8 is not a predictive biomarker for the development of the acute promyelocytic leukemia differentiation syndrome. BMC CANCER, v. 20, n. 1, AUG 28 2020. (13/08135-2, 16/02713-2, 17/23117-1)

THOME, CAROLINA HASSIBE; FERREIRA, GERMANO AGUIAR; PEREIRA-MARTINS, DIEGO ANTONIO; DOS SANTOS, GUILHERME AUGUSTO; ALMEIDA-SILVEIRA, DOUGLAS R.; WEINHAUSER, ISABEL; DE SOUZA, GUSTAVO ANTONIO; HOUTSMA, ROOS; SCHURINGA, JAN JACOB; REGO, EDUARDO M.; et al. The Expression of NTAL and Its Protein Interactors Is Associated With Clinical Outcomes in Acute Myeloid Leukemia. MOLECULAR & CELLULAR PROTEOMICS, v. 20, 2021. (17/23117-1, 13/07675-3, 15/09228-0)

SILVEIRA, DOUGLAS R. A.; QUEK, LYNN; SANTOS, ITAMAR S.; CORBY, ANNA; COELHO-SILVA, JUAN L.; PEREIRA-MARTINS, DIEGO A.; VALLANCE, GRANT; BROWN, BENJAMIN; NARDINELLI, LUCIANA; SILVA, WELLINGTON F.; et al. Integrating clinical features with genetic factors enhances survival prediction for adults with acute myeloid leukemia. BLOOD ADVANCES, v. 4, n. 10, p. 2339-2350, MAY 26 2020. (16/23191-4, 17/23117-1)

ERDEM, AYSEGUL; MARIN, SILVIA; PEREIRA-MARTINS, DIEGO A.; CORTES, ROLDAN; CUNNINGHAM, ALAN; PRUIS, MAURIEN G.; DE BOER, BAUKE; VAN DEN HEUVEL, FIONA A. J.; GEUGIEN, MARJAN; WIERENGA, ALBERTUS T. J.; et al. The Glycolytic Gatekeeper PDK1 defines different metabolic states between genetically distinct subtypes of human acute myeloid leukemia. NATURE COMMUNICATIONS, v. 13, n. 1, p. 16-pg., 2022-03-01. (17/23117-1)

ORTIZ ROJAS, CESAR ALEXANDER; COSTA-NETO, ABEL; PEREIRA-MARTINS, DIEGO A.; LE, DUY MINH; STERNADT, DOMINIQUE; WEINHAEUSER, ISABEL; HULS, GERWIN; SCHURINGA, JAN JACOB; MAGALHAES REGO, EDUARDO. High ME1 Expression Is a Molecular Predictor of Post-Transplant Survival of Patients with Acute Myeloid Leukemia. CANCERS, v. 15, n. 1, p. 17-pg., 2023-01-01. (17/08430-5, 17/23117-1, 15/09228-0, 13/08135-2)

PEREIRA-MARTINS, DIEGO A.; WEINHAUSER, ISABEL; COELHO-SILVA, JUAN LUIZ; FRANCA-NETO, PEDRO L.; ALMEIDA, LUCIANA Y.; BIANCO, THIAGO M.; SILVA, CLEIDE L.; FRANCA, RAFAEL F.; TRAINA, FABIOLA; REGO, EDUARDO M.; et al. MLL5 improves ATRA driven differentiation and promotes xenotransplant engraftment in acute promyelocytic leukemia model. CELL DEATH & DISEASE, v. 12, n. 4, p. 14-pg., 2021-04-06. (13/08135-2, 17/23117-1, 15/09228-0, 16/23191-4)

PEREIRA-MARTINS, DIEGO A.; COELHO-SILVA, JUAN L.; WEINHAUSER, ISABEL; FRANCA-NETO, PEDRO L.; SILVEIRA, DOUGLAS R.; ORTIZ, CESAR; MOREIRA-AGUIAR, AMANDA; LIMA, MARINUS M.; KOURY, LUISA C.; DE MELO, RAUL A.; et al. Clinical significance of mitochondrial DNA content in acute promyelocytic leukaemia. British Journal of Haematology, v. 200, n. 2, p. 5-pg., 2022-10-20. (13/08135-2, 16/23191-4, 15/09228-0, 17/23117-1)

Academic Publications

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

MARTINS, Diego Antonio Pereira. Evaluation of the TP53/TP73 pathway in the engraftment of primary acute promyelocytic leukemia cells using a xenotransplantation model. 2022. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) Ribeirão Preto.