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

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)

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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)
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, . (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., . (13/08135-2, 14/50947-7, 15/23555-3, 18/19714-7, 15/21866-1, 14/04234-9)
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, . (15/21866-1)
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., . (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., . (14/50947-7, 15/21866-1, 18/19714-7, 15/23555-3, 15/00658-1, 13/08135-2, 18/01756-5)
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, . (15/21866-1)
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, . (11/11822-6, 15/21866-1)
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., . (21/06841-3, 15/21866-1)

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