Cytokine-mediated regulation of normal and neoplastic hematopoietic stem cells by natural killer cells

• Grant number: 15/21866-1
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: September 01, 2016
• End date: February 28, 2021
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Lorena Lôbo de Figueiredo Pontes
• Grantee: Lorena Lôbo de Figueiredo Pontes
• Host Institution: Hemocentro de Ribeirão Preto. Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da USP (HCMRP). Ribeirão Preto , SP, Brazil
• City of the host institution: Ribeirão Preto
• Associated researchers: Belinda Pinto Simoes ; Eduardo Magalhães Rego
• Associated research grant(s): 21/06841-3 - Molecular and phenotypical mechanisms driving immune evasion in myeloid malignancies, AP.JP2
• Associated scholarship(s): 18/00081-4 - Training in characterization of the transgenic murine model Jak2V617F, BP.TT; 16/17611-0 - Identification of regulation mechanisms of natural killer cells by factor transcript C/EBPG (CCAAT/ Enhancer Binding Protein Gamma), BP.MS

Abstract

Considering that hematopoietic stem cells (HSC) directly respond to cytokines like IFNg, TNFa, TGFb, GM-CSF, MIP1, IL-10 and others, we hypothesized that Natural Killer (NK)-mediated cytokine production could regulate HSC function (subproject 1) and that its deregulation may favor malignant transformation (subproject 2). To address the role of NK function in normal hematopoiesis, we will co-cultivate wild type (wt) and Cebpg KO deficient NK cells and normal HSCs and asses the effects of NK cells on HSC's proliferation and hematological reconstitution potential. We plan to investigatee the mechanisms involved in such regulation by the use of gene expression and cytokine profile assays of NK cells. In the second part of the project, we plan to study the regulation of myeloproliferative neoplasms (MPN) stem cells by NK cell activity by the use of a conditional knockin Jak2V617F mutation (Jak2VF) murine model, which faithfully resemble the main clinical and laboratorial characteristics of human Polycythemia Vera. We recently found that Jak2VF mice have lower numbers of NK cells as compared to controls and aim to study the immunophenotype, receptor activation, cytokine profile and function of the Jak2VF NK subset. To further characterize NK activity in this model, we intend to co-culture Jak2WT and Jak2VF NK cells with HSCs and evaluate its proliferation, differentiation and self-renewal properties. In summary, with this proposal, we intend to study the interplay between HSCs and NK cells, that may collaborate in the task of regulating the normal and malignant hematopoiesis, aiming to identify new therapeutic targets that may regulate this complex interaction. (AU)

Scientific publications

(8)

(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)

TAKEI, HISASHI; COELHO-SILVA, JUAN LUIZ; LEAL, CRISTINA TAVARES; ARANTES ROCHA, ADRIANA QUEIROZ; BIANCO, THIAGO MANTELLO; WELNER, ROBERT S.; MISHIMA, YUTA; KOBAYASHI, IKEI S.; MULLALLY, ANN; LIMA, KELI; et al. uppression of multiple anti-apoptotic BCL2 family proteins recapitulates the effects of JAK2 inhibitors in JAK2V617F driven myeloproliferative neoplasm. Cancer Science, v. 113, n. 2, DEC 2021. (11/11822-6, 15/21866-1)

DE ALMEIDA, FELIPE CAMPOS; BERZOTI-COELHO, MARIA G.; TORO, DIANA MOTA; CACEMIRO, MAIRA DA COSTA; BASSAN, VITOR LEONARDO; BARRETTO, GABRIEL DESSOTTI; MARQUES GARIBALDI, PEDRO MANOEL; PALMA, LEONARDO CARVALHO; DE FIGUEIREDO-PONTES, LORENA LOBO; SORGI, CARLOS ARTERIO; et al. Bioactive Lipids as Chronic Myeloid Leukemia's Potential Biomarkers for Disease Progression and Response to Tyrosine Kinase Inhibitors. FRONTIERS IN IMMUNOLOGY, v. 13, p. 8-pg., 2022-04-13. (14/50947-7, 15/21866-1, 18/19714-7, 15/23555-3, 15/00658-1, 13/08135-2, 18/01756-5)

COSTA, AMANDA FERNANDES DE OLIVEIRA; MARANI, LETICIA OLOPS; BIANCO, THIAGO MANTELLO; ARANTES, ADRIANA QUEIROZ; LOPES, IZABELA APARECIDA; PEREIRA-MARTINS, DIEGO ANTONIO; PALMA, LEONARDO CARVALHO; SCHEUCHER, PRISCILA SANTOS; SCHIAVINATO, JOSIANE LILIAN DOS SANTOS; BINELLI, LARISSA SARRI; et al. Altered distribution and function of NK-cell subsets lead to impaired tumor surveillance in JAK2V617F myeloproliferative neoplasms. FRONTIERS IN IMMUNOLOGY, v. 13, p. 15-pg., 2022-09-23. (21/06841-3, 15/21866-1)

DA COSTA, VICTOR E. F.; DE OLIVEIRA, RAFAEL D.; TRAINA, FABIOLA; CHAHUD, FERNANDO; PALMA, LEONARDO C.; DE FIGUEIREDO-PONTES, LORENA L.. Co-occurrence of BCR-ABL1-positive chronic myeloid leukaemia and CALR-mutated essential thrombocythaemia. British Journal of Haematology, v. 188, n. 3, NOV 2019. (15/21866-1)

KARDOSOVA, MIROSLAVA; ZJABLOVSKAJA, POLINA; DANEK, PETR; ANGELISOVA, PAVLA; DE FIGUEIREDO-PONTES, LORENA LOBO; WELNER, ROBERT S.; BRDICKA, TOMAS; LEE, SANGHOON; TENEN, DANIEL G.; ALBERICH-JORDA, MERITXELL. C/EBP gamma is dispensable for steady-state and emergency granulopoiesis. Haematologica, v. 103, n. 8, p. E331-E335, JUL 31 2018. (15/21866-1)

CACEMIRO, MAIRA DA COSTA; COMINAL, JUCARA GASTALDI; PEREIRA, LUIZ MIGUEL; BERZOTI-COELHO, MARIA GABRIELA; BERBEL, GIOVANA MICHELASSI; BARONI, LUCIANA; MALTA, TATHIANE; TOGNON, RAQUEL; NUNES, NATALIA DE SOUZA; SOUTO, ELIZABETH XISTO; et al. Hippo pathway-related genes expression is deregulated in myeloproliferative neoplasms. MEDICAL ONCOLOGY, v. 39, n. 5, p. 11-pg., 2022-05-01. (13/08135-2, 14/50947-7, 15/23555-3, 18/19714-7, 15/21866-1, 14/04234-9)

DE FIGUEIREDO-PONTES, LORENA LOBO; ADAMCOVA, MIROSLAVA K.; WELNER, ROBERT S.; TENEN, DANIEL G.; ALBERICH-JORDA, MERITXELL. Response to NK cell content does not seem to influence engraftment in ex vivo T cell depleted haploidentical stem cell transplantation. STEM CELL REPORTS, v. 17, n. 3, p. 2-pg., 2022-03-08. (15/21866-1)

DE FIGUEIREDO-PONTES, LORENA LOBO; ADAMCOVA, MIROSLAVA K.; GRUSANOVIC, SRDJAN; KUZMINA, MARIA; LOPES, IZABELA APARECIDA; DE OLIVEIRA COSTA, AMANDA FERNANDES; ZHANG, HONG; STRNAD, HYNEK; LEE, SANGHOON; MOUDRA, ALENA; et al. Improved hematopoietic stem cell transplantation upon inhibition of natural killer cell-derived interferon-gamma. STEM CELL REPORTS, v. 16, n. 8, p. 1999-2013, AUG 10 2021. (15/21866-1)