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Bone Marrow Mesenchymal Stromal Cells deregulation effect on BCR-ABL1-Myeloproliferative Neoplasms pathophysiology and progression

Abstract

Myeloproliferative neoplasms (MPN) are hematological disorders characterized by increased cell proliferation and accumulation of mature and precursor myeloid cells in bone marrow and peripheral blood independently of cytokine stimuli and growth factors. The discovery of genetic mutations linked to this disorders development, since 2005, has been contributed to the understanding of the pathophysiology of MPN. However, despite the knowledge accumulated in the last decade, the cellular and molecular mechanisms involved in MPN development and progression to myelofibrosis and acute myeloid leukemia should be elucidated. MPN were considered pre-leukemic onco-inflammatory disorders characterized by a high pro-inflammatory profile. This inflammatory status seems to be important for disease pathophysiology and prognosis. Indeed, there are some evidences that the pro-inflammatory pathway could impair the pre-leukemic disease progression, but also increase the thrombosis risk and the constitutional symptoms in MPN patients. Although the deregulated hematopoiesis in MPN is mainly attributed to somatic mutations in the hematopoietic stem cell (HSC), the abnormalities in the immune system and in mesenchymal stromal cells (MSC) from bone marrow (BM) microenvironment seems to contribute to disease pathophysiology and progression. The BM stromal microenvironment is composed by extracellular matrix and specialized cells, with emphasis on the MSC responsible for the maintenance of HSC pool and HSC stemness potential. MSC contribute to HSC quiescence, protecting them from pro-apoptotic and differentiation stimuli. Thus, the MSC alteration may participate in HSC malignant transformation, leading to MPN progression to secondary MF or acute myeloid leukemia (AML).We speculate that the deregulated MSC immunomodulatory profile may contribute to the MPN pathophysiology and progression. We hypothesize that MSC is capable of changing the hematopoietic niche microenvironment and its immune function by releasing abnormal cytokines, chemokines, lipid mediators and growth factors, favoring the neo-angiogenesis and the leukemia stem cells (LSC) emergence. Thus, in this research we will evaluate the MSC immunomodulatory, pro-angiogenic and anti-clonogenic properties in MPN patients and in PV mice model who progress to MF. The major aim of this study is to describe the crosstalk between the hematopoietic niche immune deregulation and MPN pathophisiology and progression to MF/AML. We believe that these new knowledge will contribute to design new effective therapy to prevent disease progression and to treat MPN in pre-leukemic phase. (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)
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)
COMINAL, JUCARA GASTALDI; CACEMIRO, MAIRA DA COSTA; BERZOTI-COELHO, MARIA GABRIELA; PEREIRA, ILLY ENNE GOMES; FRANTZ, FABIANI GAI; SOUTO, ELIZABETH XISTO; COVAS, DIMAS TADEU; FIGUEIREDO-PONTES, LORENA LOBO DE; OLIVEIRA, MARIA CAROLINA; MALMEGRIM, KELEN CRISTINA RIBEIRO; et al. Bone Marrow Soluble Mediator Signatures of Patients With Philadelphia Chromosome-Negative Myeloproliferative Neoplasms. FRONTIERS IN ONCOLOGY, v. 11, . (13/08135-2, 14/50947-7, 18/01756-5, 18/19714-7, 15/23555-3)
CACEMIRO, MAIRA DA COSTA; COMINAL, JUCARA GASTALDI; BERZOTI-COELHO, MARIA GABRIELA; TOGNON, RAQUEL; NUNES, NATALIA DE SOUZA; SIMOES, BELINDA; PEREIRA, ITALO SOUSA; CARLOS, DANIELA; FACCIOLI, LUCIA HELENA; DE FIGUEIREDO-PONTES, LORENA LOBO; et al. Differential cytokine network profile in polycythemia vera and secondary polycythemia. SCIENTIFIC REPORTS, v. 10, n. 1, . (15/23555-3, 17/23501-6, 18/01756-5, 14/50947-7, 18/19714-7, 13/08135-2)
COMINAL, JUCARA GASTALDI; CACEMIRO, MAIRA DA COSTA; PINTO-SIMOES, BELINDA; KOLB, HANS-JOCHEM; RIBEIRO MALMEGRIM, KELEN CRISTINA; DE CASTRO, FABIOLA ATTIE. Emerging Role of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Pathogenesis of Haematological Malignancies. STEM CELLS INTERNATIONAL, . (13/08135-2, 14/50947-7, 18/19714-7, 18/01756-5)
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)
GOMES PEREIRA, ILLY ENNE; CACEMIRO, MAIRA DA COSTA; COMINAL, JUCARA GASTALDI; BARRETTO, GABRIEL DESSOTTI; DE CASTRO, FABIOLA ATTIE. Role of Endothelial Cells in Hematological Malignancies. EURASIAN JOURNAL OF MEDICINE AND ONCOLOGY, v. 6, n. 3, p. 9-pg., . (13/08135-2, 18/19714-7, 18/01756-5, 14/50947-7)
BASSAN, VITOR LEONARDO; BARRETTO, GABRIEL DESSOTTI; DE ALMEIDA, FELIPE CAMPOS; BONINI PALMA, PATRICIA VIANNA; BINELLI, LARISSA SARRI; LETTIERI DA SILVA, JOAO PAULO; FONTANARI, CAROLINE; CASTRO, RICARDO CARDOSO; DE FIGUEIREDO PONTES, LORENA LOBO; FRANTZ, FABIANI GAI; et al. Philadelphia-negative myeloproliferative neoplasms display alterations in monocyte subpopulations frequency and immunophenotype. MEDICAL ONCOLOGY, v. 39, n. 12, p. 12-pg., . (18/19714-7, 13/08135-2, 19/18013-8)
COMINAL, JUCARA GASTALDI; CACEMIRO, MAIRA DA COSTA; PINTO-SIMOES, BELINDA; KOLB, HANS-JOCHEM; RIBEIRO MALMEGRIM, KELEN CRISTINA; DE CASTRO, FABIOLA ATTIE. Emerging Role of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Pathogenesis of Haematological Malignancies. STEM CELLS INTERNATIONAL, v. 2019, p. 12-pg., . (13/08135-2, 18/19714-7, 18/01756-5, 14/50947-7)

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