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.
Studies have shown that the clinical impact of Janus kinase 2 (JAK2) inhibitors in primary myelofibrosis patients is due to the regulation of cytokine levels, suggesting that cytokine profiles might ...play a critical role in myeloproliferative neoplasms (MPNs) physiopathology. In this study, we compared the plasma cytokine profiles of polycythemia vera (PV) patients and essential thrombocythemia (ET) patients as a function of their JAK2 V617F status and the presence of thrombohemorrhagic complications. Using a multiplex cytokine assay, cytokine measurements were taken of the plasma of 17 PV patients and 21 ET patients. Twenty-two of these patients (10 PV and 12 ET) experienced at least one thrombohemorrhagic manifestation before diagnosis. We showed that cytokine levels were significantly increased in PV and ET patients compared with normal values and that several positive correlations existed between the cytokine concentrations and the biological parameters in each MPN. The comparison between the cytokine profiles of ET and PV patients showed a statistically significant increase of interleukin (IL)-4, IL-8, granulocyte macrophage–colony stimulating factor, interferon -γ, monocyte chemotactic protein -1, platelet derived growth factor-BB, and vascular endothelial growth factor in the ET group. Only tumor necrosis factor-α and platelet derived growth factor-BB were specifically impacted by the JAK2 V617F status of the PV and ET patients, respectively, suggesting that there are both JAK2 V617F–driven and JAK2 V617F–independent inflammatory responses in MPNs. We also showed that the subgroup of PV patients with vascular complications displayed significantly different concentrations of IL-12(p70) and granulocyte macrophage–colony stimulating factor compared with patients without vascular complications. Altogether, these data suggest that cytokine measurement might be useful for the clinical and therapeutic stratification of PV and ET patients.
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.
Acute myeloid leukemia (AML) remains a disease of gloomy prognosis despite intense efforts to understand its molecular foundations and to find efficient treatments. In search of new characteristic ...features of AML blasts, we first examined experimental conditions supporting the amplification of hematological CD34+ progenitors ex vivo. Both AML blasts and healthy progenitors heavily depended on iron availability. However, even if known features, such as easier engagement in the cell cycle and amplification factor by healthy progenitors, were observed, multiplying progenitors in a fully defined medium is not readily obtained without modifying their cellular characteristics. As such, we measured selected molecular data including mRNA, proteins, and activities right after isolation. Leukemic blasts showed clear signs of metabolic and signaling shifts as already known, and we provide unprecedented data emphasizing disturbed cellular iron homeostasis in these blasts. The combined quantitative data relative to the latter pathway allowed us to stratify the studied patients in two sets with different iron status. This categorization is likely to impact the efficiency of several therapeutic strategies targeting cellular iron handling that may be applied to eradicate AML blasts.
Several studies have linked bad prognoses of acute myeloid leukemia (AML) to the ability of leukemic cells to reprogram their metabolism and, in particular, their lipid metabolism. In this context, ...we performed "in-depth" characterization of fatty acids (FAs) and lipid species in leukemic cell lines and in plasma from AML patients. We firstly showed that leukemic cell lines harbored significant differences in their lipid profiles at steady state, and that under nutrient stress, they developed common mechanisms of protection that led to variation in the same lipid species; this highlights that the remodeling of lipid species is a major and shared mechanism of adaptation to stress in leukemic cells. We also showed that sensitivity to etomoxir, which blocks fatty acid oxidation (FAO), was dependent on the initial lipid profile of cell lines, suggesting that only a particular "lipidic phenotype" is sensitive to the drug targeting of FAO. We then showed that the lipid profiles of plasma samples from AML patients were significantly correlated with the prognosis of patients. In particular, we highlighted the impact of phosphocholine and phosphatidyl-choline metabolism on patients' survival. In conclusion, our data show that balance between lipid species is a phenotypic marker of the diversity of leukemic cells that significantly influences their proliferation and resistance to stress, and thereby, the prognosis of AML patients.
Introduction
Acute myeloid leukemia (AML) is characterized by a set of malignant proliferations leading to an accumulation of blasts in the bone marrow and blood. The prognosis is pejorative due to ...the molecular complexity and pathways implicated in leukemogenesis.
Objectives
Our research was focused on comparing the metabolic profiles of leukemic cells in basal culture and deprivation conditions to investigate their behaviors under metabolic stress.
Methods
We performed untargeted metabolomics using
1
H HRMAS-NMR. Five human leukemic cell lines—KG1, K562, HEL, HL60 and OCIAML3—were studied in the basal and nutrient deprivation states. A multivariate analysis of the metabolic profile was performed to find over- or under- expressed metabolites in the different cell lines, depending on the experimental conditions.
Results
In the basal state, each leukemic cell line exhibited a specific metabolic signature related to the diversity of AML subtypes represented and their phenotypes. When cultured in a serum-free medium, they showed quick metabolic adaptation and continued to proliferate and survive despite the lack of nutrients. Low apoptosis was observed. Increased phosphocholine and glutathione was a common feature of all the observed cell lines, with the maximum increase in these metabolites at 24 h of culture, suggesting the involvement of lipid metabolism and oxidative stress regulators in the survival mechanism developed by the leukemic cells.
Conclusions
Our study provides new insights into the metabolic mechanisms in leukemogenesis and suggests a hierarchy of metabolic pathways activated within leukemic cells, some dependent on their genotypes and others conserved among the subtypes but commonly induced under micro-environmental stress.
Iron is an essential nutrient which must be provided in sufficient amounts to support growth of eukaryotic cells. All organisms devote specialized pathways to ensure proper delivery. Yet, a ...quantitative assessment of the intra-cellular iron concentration needed to allow the cell cycle to proceed in mammalian cells is missing. Starting from iron-depleted cell lines or primary hematopoietic progenitors prepared with clinically implemented iron chelators, replenishment via transferrin and other iron sources has been quantitatively monitored through the main endogenous markers of the cellular iron status, namely proteins involved in the uptake (transferrin receptor), the storage (ferritin), and the sensing (Iron Regulatory Proteins) of iron. When correlated with measurements of iron concentrations and indicators of growth, this minimally intrusive approach provided an unprecedented estimate of the intracellular iron concentration acting upon iron-centered regulatory pathways. The data were analyzed with the help of a previously developed theoretical treatment of cellular iron regulation. The minimal cellular iron concentration required for cell division was named functional iron concentration (FIC) to distinguish it from previous estimates of the cellular labile iron. The FIC falls in the low nanomolar range for all studied cells, including hematopoietic progenitors. These data shed new light on basic aspects of cellular iron homeostasis by demonstrating that sensing and regulation of iron occur well below the concentrations requiring storage or becoming noxious in pathological conditions. The quantitative assessment provided here is relevant for monitoring treatments of conditions in which iron provision must be controlled to avoid unwanted cellular proliferation.
Display omitted
•Growth of mammalian cells is stopped by iron withdrawal with chelators.•Re-entry in the cell cycle occurs with transferrin-bound iron in the nM range.•The functional iron concentration is detected before the need of storage or export.•The functional iron concentration is a key parameter for the growth of cancer cells.
A newborn girl had typical “blueberry muffin” skin lesions, which shows histopathologic features of monocytic leukemia cutis. The systemic leukemia was demonstrated after one month of life. She was ...treated by chemotherapy, including induction and three consolidation cures, according to the ELAM02 protocol, which led to complete remission. This case report with congenital form of AML5 cutaneous localization, preceding systemic involvement, with a 5‐year follow‐up and positive outcome is remarkable.
Apart from well-known genetic abnormalities, several studies have reported variations in protein expression in Philadelphia-negative 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
(
presence and
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
granulocytes compared with
wild type and independently of the
allele burden. Finally, it was demonstrated, in a Ba/F3 cell model, that increased calreticulin expression was directly linked to
and could be regulated by JAK2 kinase inhibitors.
In conclusion, these results reveal proteome alterations in MPN granulocytes depending on the phenotype and genotype of patients, highlighting new oncogenic mechanisms associated with
mutations and overexpression of calreticulin.
.
PDF
