23 research outputs found
Circulating Cytokine Levels as Markers of Inflammation in Philadelphia Negative Myeloproliferative Neoplasms: Diagnostic and Prognostic Interest
Quantitative Proteome Heterogeneity in Myeloproliferative Neoplasm Subtypes and Association with JAK2 Mutation Status
Apart from well-known genetic abnormalities, several studies have reported variations in protein expression in Philadelphianegative myeloproliferative neoplasm (MPN) patients that could contribute toward their clinical phenotype. In this context, a quantitative mass spectrometry proteomics protocol was used to identify differences in the granulocyte proteome with the goal to characterize the pathogenic role of aberrant protein expression in MPNs. LC/MS-MS (LTQ Orbitrap) coupled to iTRAQ labeling showed significant and quantitative differences in protein content among various MPN subtypes [polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF)], and according to the genetic status of JAK2 (JAK2V617F presence and JAK2V617F allele burden). A number of differentially expressed proteins were identified, with the most frequent being members of the RAS GTPase family and oxidative stress regulatory proteins. Subsequent analysis found that calreticulin (CALR), known to be involved in calcium homeostasis and apoptotic signaling, was overexpressed in JAK2V617F granulocytes compared with JAK2 wild type and independently of the JAK2V617F allele burden. Finally, it was demonstrated, in a Ba/F3 cell model, that increased calreticulin expression was directly linked to JAK2V617F and could be regulated by JAK2 kinase inhibitors. Implications: In conclusion, these results reveal proteome alterations in MPN granulocytes depending on the phenotype and genotype of patients, highlighting new oncogenic mechanisms associated with JAK2 mutations and overexpression of calreticulin
Circulating Cytokine Levels as Markers of Inflammation in Philadelphia Negative Myeloproliferative Neoplasms: Diagnostic and Prognostic Interest
Impacts cliniques et physiopathologiques de l'équilibre redox et de la protéine S100A8 extracellulaire dans les leucémies aiguës myéloïdes de novo de l'adulte (hors LAM3)
Acute myeloid leukemia (AML) is characterized by clonal expansion of leukemic(s) cell(s) blocked at an early stage of maturation. Despite therapeutic advances, their prognosis remains poor and therapeutic improvements are needed. In AML, reactive oxygen species (ROS) are considered to contribute to leukemogenesis and, on the opposite, standard chemotherapies exert cytotoxicity via ROS. In addition, the redox balance acts on metabolic dysregulation in AML and depends on many regulators, such as S100A8 protein, associated with worst prognostic in AML and known to stimulate NADPH oxidase.In this context, this work focuses on oxidative disorders, and S100A8 expression in bone marrow microenvironment according to clinical-biological characteristics and evaluate their prognostic impact in AML. In addition, we investigated the impact of exogenous S100A8 on ROS production, mitochondrial respiration, and metabolism in leukemia cell lines.In a cohort of 84 de novo AML at diagnosis, we demonstrate the existence of redox balance disorders on leukemic cells, on normal cells from bone marrow microenvironment, and on antioxidant systems (SOD, GPX, glutathione ...). In addition, ROS production observed in response to mitochondrial modulators indirectly reflects mitochondrial functionality plays a prognostic role independent of the current prognostic factors. The analysis of S100A8 in bone marrow plasmas shows a higher expression in AML than in healthy controls or other hematological neoplasms. This hyperexpression is predominantly of monocytic origin and is associated with molecular abnormalities of good prognosis such as (inv (16), NPM1) or with a subgroup of mutated FLT3-ITD patients with better survival. Finally, the study of S100A8 on leukemia cell lines highlights its heterogeneous effect on cell growth, apoptosis, ROS production and on NOX regulation. Furthermore, we observe a S100A8-phosphocholine change which remains to be explored.In conclusion, this work provides original information on bio-energetic balance in AML and their prognostic impacts, emphasizing that these metabolic alterations impact AML prognosis through complex interactions.Les leucémies aigues myéloïdes (LAM) sont caractérisées par une expansion clonale de cellule(s) souche(s) leucémique(s) bloquée à un stade précoce de maturation. Malgré les avancées thérapeutiques, leur pronostic reste sombre et des progrès thérapeutiques doivent encore être réalisés. Dans les LAM, les espèces réactives de l’oxygène (ROS) sont considérées comme, d’une part, participant à la leucémogenèse et, d’autre part, comme hautement impliquées dans la sensibilité aux chimiothérapies conventionnelles. Par ailleurs, l’équilibre redox qui participe aux dérégulations métaboliques associées au processus leucémique, dépend de nombreux régulateurs, dont la protéine S100A8, protéine connue pour son action stimulatrice sur la NADPH oxydase et sa valeur pronostique dans les LAM.Ce travail s’est donc intéressé à la caractérisation des désordres oxydatifs dans les LAM afin d’évaluer leur impact clinico-biologique, et d’autre part au rôle de la sécrétion de la S100A8 dans le microenvironnement médullaire. De plus, à partir de lignées leucémiques, nous avons étudié l’impact de la S100A8 exogène sur la production de ROS, la respiration mitochondriale et le métabolome des cellules blastiques.A partir d’une cohorte de 84 patients atteints de LAM de novo au diagnostic, nous avons mis en évidence des désordres de l’équilibre redox à la fois dans les cellules leucémiques, dans les cellules normales de l’environnement médullaire ainsi que sur les systèmes régulateurs antioxydants (SOD, GPX, glutathion…). De plus, nous avons montré que la production des ROS observée en réponse à des modulateurs de la mitochondrie, qui reflète indirectement la fonctionnalité mitochondriale, joue un rôle pronostique indépendant des facteurs pronostiques habituels. L’analyse de la S100A8 dans les plasmas médullaires montre une expression augmentée dans les LAM, d’origine monocytaire majoritairement et est associée à des anomalies moléculaires de bon pronostic (inv(16), NPM1) ou un sous-groupe de patients FLT3-ITD mutés présentant une meilleure survie. Enfin, l’étude de la S100A8 sur les lignées leucémiques a permis de mettre en évidence la diversité de ses effets sur la croissance cellulaire, l’apoptose, la production de ROS ainsi qu’une variation métabolique de la phosphocholine dont les mécanismes restent à explorer.En conclusion, mon travail apporte des éléments originaux sur les particularités de l’équilibre bio-énergétique dans les LAM. Il souligne, que l’impact de ses dérégulations sur le pronostic des patients résulte de la combinaison d’un ensemble de facteurs métaboliques, qui doivent être appréhender dans leur globalité pour une meilleure efficacité thérapeutique
Clinical and physiopathological roles of redox balance and of extracellular S100A8 protein in de novo adult acute myeloid leukemia (APL excluded)
Les leucémies aigues myéloïdes (LAM) sont caractérisées par une expansion clonale de cellule(s) souche(s) leucémique(s) bloquée à un stade précoce de maturation. Malgré les avancées thérapeutiques, leur pronostic reste sombre et des progrès thérapeutiques doivent encore être réalisés. Dans les LAM, les espèces réactives de l’oxygène (ROS) sont considérées comme, d’une part, participant à la leucémogenèse et, d’autre part, comme hautement impliquées dans la sensibilité aux chimiothérapies conventionnelles. Par ailleurs, l’équilibre redox qui participe aux dérégulations métaboliques associées au processus leucémique, dépend de nombreux régulateurs, dont la protéine S100A8, protéine connue pour son action stimulatrice sur la NADPH oxydase et sa valeur pronostique dans les LAM.Ce travail s’est donc intéressé à la caractérisation des désordres oxydatifs dans les LAM afin d’évaluer leur impact clinico-biologique, et d’autre part au rôle de la sécrétion de la S100A8 dans le microenvironnement médullaire. De plus, à partir de lignées leucémiques, nous avons étudié l’impact de la S100A8 exogène sur la production de ROS, la respiration mitochondriale et le métabolome des cellules blastiques.A partir d’une cohorte de 84 patients atteints de LAM de novo au diagnostic, nous avons mis en évidence des désordres de l’équilibre redox à la fois dans les cellules leucémiques, dans les cellules normales de l’environnement médullaire ainsi que sur les systèmes régulateurs antioxydants (SOD, GPX, glutathion…). De plus, nous avons montré que la production des ROS observée en réponse à des modulateurs de la mitochondrie, qui reflète indirectement la fonctionnalité mitochondriale, joue un rôle pronostique indépendant des facteurs pronostiques habituels. L’analyse de la S100A8 dans les plasmas médullaires montre une expression augmentée dans les LAM, d’origine monocytaire majoritairement et est associée à des anomalies moléculaires de bon pronostic (inv(16), NPM1) ou un sous-groupe de patients FLT3-ITD mutés présentant une meilleure survie. Enfin, l’étude de la S100A8 sur les lignées leucémiques a permis de mettre en évidence la diversité de ses effets sur la croissance cellulaire, l’apoptose, la production de ROS ainsi qu’une variation métabolique de la phosphocholine dont les mécanismes restent à explorer.En conclusion, mon travail apporte des éléments originaux sur les particularités de l’équilibre bio-énergétique dans les LAM. Il souligne, que l’impact de ses dérégulations sur le pronostic des patients résulte de la combinaison d’un ensemble de facteurs métaboliques, qui doivent être appréhender dans leur globalité pour une meilleure efficacité thérapeutique.Acute myeloid leukemia (AML) is characterized by clonal expansion of leukemic(s) cell(s) blocked at an early stage of maturation. Despite therapeutic advances, their prognosis remains poor and therapeutic improvements are needed. In AML, reactive oxygen species (ROS) are considered to contribute to leukemogenesis and, on the opposite, standard chemotherapies exert cytotoxicity via ROS. In addition, the redox balance acts on metabolic dysregulation in AML and depends on many regulators, such as S100A8 protein, associated with worst prognostic in AML and known to stimulate NADPH oxidase.In this context, this work focuses on oxidative disorders, and S100A8 expression in bone marrow microenvironment according to clinical-biological characteristics and evaluate their prognostic impact in AML. In addition, we investigated the impact of exogenous S100A8 on ROS production, mitochondrial respiration, and metabolism in leukemia cell lines.In a cohort of 84 de novo AML at diagnosis, we demonstrate the existence of redox balance disorders on leukemic cells, on normal cells from bone marrow microenvironment, and on antioxidant systems (SOD, GPX, glutathione ...). In addition, ROS production observed in response to mitochondrial modulators indirectly reflects mitochondrial functionality plays a prognostic role independent of the current prognostic factors. The analysis of S100A8 in bone marrow plasmas shows a higher expression in AML than in healthy controls or other hematological neoplasms. This hyperexpression is predominantly of monocytic origin and is associated with molecular abnormalities of good prognosis such as (inv (16), NPM1) or with a subgroup of mutated FLT3-ITD patients with better survival. Finally, the study of S100A8 on leukemia cell lines highlights its heterogeneous effect on cell growth, apoptosis, ROS production and on NOX regulation. Furthermore, we observe a S100A8-phosphocholine change which remains to be explored.In conclusion, this work provides original information on bio-energetic balance in AML and their prognostic impacts, emphasizing that these metabolic alterations impact AML prognosis through complex interactions
Pathogenic Roles of S100A8 and S100A9 Proteins in Acute Myeloid and Lymphoid Leukemia: Clinical and Therapeutic Impacts
Deregulations of the expression of the S100A8 and S100A9 genes and/or proteins, as well as changes in their plasma levels or their levels of secretion in the bone marrow microenvironment, are frequently observed in acute myeloblastic leukemias (AML) and acute lymphoblastic leukemias (ALL). These deregulations impact the prognosis of patients through various mechanisms of cellular or extracellular regulation of the viability of leukemic cells. In particular, S100A8 and S100A9 in monomeric, homodimeric, or heterodimeric forms are able to modulate the survival and the sensitivity to chemotherapy of leukemic clones through their action on the regulation of intracellular calcium, on oxidative stress, on the activation of apoptosis, and thanks to their implications, on cell death regulation by autophagy and pyroptosis. Moreover, biologic effects of S100A8/9 via both TLR4 and RAGE on hematopoietic stem cells contribute to the selection and expansion of leukemic clones by excretion of proinflammatory cytokines and/or immune regulation. Hence, the therapeutic targeting of S100A8 and S100A9 appears to be a promising way to improve treatment efficiency in acute leukemias
Circulating Cytokine Levels as Markers of Inflammation in Philadelphia Negative Myeloproliferative Neoplasms: Diagnostic and Prognostic Interest
Cytokines are well known mediators of numerous physiological and pathological processes. They contribute to the regulation of normal hematopoiesis but increasing data suggest that they also have a clinical impact in some hematopoietic malignancies. In particular, there is evidence that cytokines are implicated in the functional symptoms of Philadelphia negative myeloproliferative neoplasms (Ph− MPNs), suggesting that evaluation of circulating levels of cytokines could be of clinical interest for the characterization of patients at the time of diagnosis and for disease prognosis. In this review, we present the current knowledge on alteration of circulating cytokine profiles in MPNs and their role in myelofibrosis pathogenesis. Phenotypic correlation, prognostic value of cytokines, and impact of JAK inhibitors are also discussed
Circulating Cytokine Levels as Markers of Inflammation in Philadelphia Negative Myeloproliferative Neoplasms: Diagnostic and Prognostic Interest
Cytokines are well known mediators of numerous physiological and pathological processes. They contribute to the regulation of normal hematopoiesis but increasing data suggest that they also have a clinical impact in some hematopoietic malignancies. In particular, there is evidence that cytokines are implicated in the functional symptoms of Philadelphia negative myeloproliferative neoplasms (Ph− MPNs), suggesting that evaluation of circulating levels of cytokines could be of clinical interest for the characterization of patients at the time of diagnosis and for disease prognosis. In this review, we present the current knowledge on alteration of circulating cytokine profiles in MPNs and their role in myelofibrosis pathogenesis. Phenotypic correlation, prognostic value of cytokines, and impact of JAK inhibitors are also discussed
The differential activation of metabolic pathways in leukemic cells depending on their genotype and micro-environmental stress
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An impressive response with larotrectinib in a patient with a papillary thyroid carcinoma harboring an SQSTM1-NTRK1 fusion
NTRK rearrangements represent a very rare genomic abnormality among all cancers but can be detected in thyroid cancer with a non-negligible frequency of 2%. Dramatic clinical responses to therapies targeting NTRK chimeric proteins are now well described in the literature. SQSTM1-NTRK1 fusions have not yet been described in a full clinical case report. We report a patient with a papillary thyroid carcinoma harboring this unique rearrangement, with an impressive clinical and radiologic response to larotrectinib, a highly specific inhibitor