Deregulation of apoptosis in acute myeloid leukemia.

Apoptosis, or programmed cell death, is central to the development and homeostasis of the hematopoietic system. Dysregulation of apoptosis plays an important role in the development of a variety of human pathologies, including cancer, autoimmune diseases and neurodegenerative disorders. Particularly, studies carried out in the last years have shown that leukemia cells invariably have abnormalities in one or more apoptotic pathways, determining a survival advantage of these cells over their normal counterpart. Furthermore, abnormalities in the apoptotic response also play a role in the development of drug resistance by leukemic cells. The identification of the different components of the apoptotic pathways has enabled the detection of various biochemical defects present in leukemic cells compared to their normal counterpart. These defects contribute to the survival advantage of the leukemic clone over the normal hematopoietic cells and are also frequently associated with a low rate of response to standard chemotherapy treatment and with poor survival. Furthermore, these findings have also lead to the identification of many potential apoptotic targets for the development of new drugs targeting anti-apoptotic molecules abnormally expressed or regulated in leukemic cells. Many of these drugs restore the sensitivity of leukemic cells to apoptotic stimuli and some of them are under investigation at a clinical level

Role of Stem Cell Factor in the Reactivation of Human Fetal Hemoglobin

In humans the switch from fetal to adult hemoglobin (HbF → HbA) takes place in the perinatal and postnatal period, determining the progressive replacement of HbF with HbA synthesis (i.e., the relative HbF content in red blood cells decreases from 80–90% to <1%). In spite of more than twenty years of intensive investigations on this classic model, the molecular mechanisms regulating the Hb switching, as well as HbF synthesis in adults, has been only in part elucidated. In adult life, the residual HbF, restricted to F cell compartment, may be reactivated up to 10–20% of total Hb synthesis in various conditions associated with “stress erythropoiesis”: this reactivation represented until now an interesting model of partial Hb switch reverse with important therapeutic implications in patients with hemoglobinopathies, and particularly in β-thalassemia. In vitro and in vivo models have led to the identification of several chemical compounds able to reactivate HbF synthesis in adult erythroid cells. Although the impact of these HbF inducers, including hypomethylating agents, histone deacetylase inhibitors and hydroxyurea, was clear on the natural history of sickle cell anemia, the benefit on the clinical course of β-thalassemia was only limited: particularly, the toxicity and the modest increase in γ-globin reactivation indicated the need for improved agents able to induce higher levels of HbF. In the present review we describe the biologic properties of Stem Cell Factor (SCF), a cytokine sustaining the survival and proliferation of erythroid cells, that at pharmacological doses acts as a potent stimulator of HbF synthesis in adult erythroid cells

New promising developments for potential therapeutic applications of high-dose ascorbate as an anticancer drug.

Vitamin C (ascorbate) is an essential dietary requirement, with fundamental redox, anti-oxidant functions at physiologic concentrations. Vitamin C is a cofactor for Fe2+ and 2-oxoglutarate-dependent dioxygenases, englobing large families of enzymes, including also epigenetic regulators of DNA and histone methylation. Importantly, vitamin C is involved in the control of the activity of TET (ten-eleven translocation) enzymes, key epigenetic regulators. For this spectrum of activities, often involving pathways deregulated in cancer cells, vitamin C possesses some pharmacologic activities that can be exploited in anticancer therapy. In particular, the capacity of pharmacological doses of vitamin C to target redox imbalance and to rescue deregulated epigenetic program observed in some cancer cells represents a consistent therapeutic potentiality. Several recent studies have identified some cancer subsets that could benefit from the pharmacological activities of vitamin C. The identification of these potentially responsive patients will help to carefully define controlled clinical trials aiming to evaluate the anticancer activity of Vitamin C

Transferrin receptor 2 is emerging as a major player in the control of iron metabolism

Abstract Our knowledge of mammalian iron metabolism has advanced dramatically over recent years. Iron is an essential element for virtually all living organisms. Its intestinal absorption and accurate cellular regulation is strictly required to ensure the coordinated synthesis of the numerous iron-containing proteins involved in key metabolic processes, while avoiding the uptake of excess iron that can lead to organ damage. A range of different proteins exist to ensure this fine control within the various tissues of the body. Among these proteins, transferrin receptor (TFR2) seems to play a key role in the regulation of iron homeostasis. Disabling mutations in TFR2 are responsible for type 3 hereditary hemochromatosis (Type 3 HH). This review describes the biological properties of this membrane receptor, with a particular emphasis paid to the structure, function and cellular localization. Although much information has been garnered on TFR2, further efforts are needed to elucidate its function in the context of the iron regulatory network

Understanding mechanisms of cancer initiation and development supports the need for an implementation of primary and secondary cancer prevention

The burden of cancer is increasing worldwide, with a continuous increase of the annual total cases. Although mortality rates due to cancer are declining in developed countries, the total number of cancer deaths continues to rise due to the increase in the number of aged people. Three main causes of cancer have been described, represented by environmental factors, hereditary factors and random factors related to defects originated during cell replication. The frequency of cancers is very different for the various tissues and there is great debate on the extent of the specific contribution of environmental factors and random factors (due to “bad luck”) to cancer development. However, there is consensus that about 50% of all cases of cancer are related to environment and are preventable. Although a part of cancers is related to intrinsic mechanisms non preventable of genetic instability, it is evident that implementation of primary and secondary prevention measures is the only affordable strategy to meet from a medical and economic point of view the tremendous pressure created on healthcare structures by the increased cancer burden. It is time to bypass the paradox of disease prevention: celebrated in principle, resisted in practice

High Doses of Vitamin C and Leukemia: In Vitro Update

Vitamin C (ascorbic acid) is an essential nutrient with a number of beneficial effects on the human body. Although the majority of mammals can synthesize their own Vitamin C, humans and a few other species, do not produce it and depend on dietary sources for their Vitamin C supply. Among its many effects on cell function and metabolism, Vitamin C has shown, in vitro, a powerful anticancer effect against a number of human tumor cell lines, including myeloid leukemia. There are many different mechanistic explanations for the anticancer/anti-leukemic effects of Vitamin C and the aim of the present review is to illustrate these mechanisms, showing the results of some preliminary in vitro investigations, and outlining their potential clinical relevance

Differential regulation of iron regulatory element-binding protein(s) in cell extracts of activated lymphocytes versus monocytes-macrophages.

The intracellular iron level exerts a negative feedback on transferrin receptor (TfR) expression in cells requiring iron for their proliferation, in contrast to the positive feedback observed in monocytes-macrophages. It has been suggested recently that modulation of TfR and ferritin synthesis by iron is mediated through a cytoplasmic protein(s) (iron regulatory element-binding protein(s) (IRE-BP)), which interacts with ferritin and TfR mRNA at the level of hairpin structures (IRE), thus leading to inhibition of transferrin mRNA degradation and repression of ferritin mRNA translation. In the present study we have evaluated in parallel the level of TfR expression, ferritin, and IRE-BP in cultures of: (i) circulating human lymphocytes stimulated to proliferate by phytohemagglutinin (PHA) and (ii) circulating human monocytes maturing in vitro to macrophages. The cells were grown in either standard or iron-supplemented culture. TfR and ferritin expression was evaluated at both the protein and mRNA level. IRE-BP activity was measured by gel retardation assay in the absence or presence of beta-mercaptoethanol (spontaneous or total IRE-BP activity, respectively). Spontaneous IRE-BP activity, already present at low level in quiescent T lymphocytes, shows a gradual and marked increase in PHA-stimulated T cells from day 1 of culture onward. This increase is directly and strictly correlated with the initiation and gradual rise of TfR expression, which is in turn associated with a decrease of ferritin content. Both the rise of TfR and spontaneous IRE-BP activity are completely inhibited in iron-supplemented T cell cultures. In contrast, the total IRE-BP level is similar in both quiescent and PHA-stimulated lymphocytes, grown in cultures supplemented or not with iron salts. Monocytes maturing in vitro to macrophages show a sharp increase of spontaneous and, to a lesser extent, total IRE-BP; the addition of iron moderately stimulates the spontaneous IRE-BP activity but not the total one. Here again, the rise of spontaneous IRE-BP from very low to high activity is strictly related to the parallel increase of TfR expression and, suprisingly, also with a very pronounced rise of ferritin expression observed at both the mRNA and protein level. It is noteworthy the effect of beta-mercaptoethanol is cell specific, i.e. the ratio of total versus spontaneous IRE-BP activity is different in activated lymphocytes and maturing monocytes.(ABSTRACT TRUNCATED AT 400 WORDS

Effective erythropoiesis and HbF reactivation induced by kit ligand in β-thalassemia

In human β-thalassemia, the imbalance between α- and non–α-globin chains causes ineffective erythropoiesis, hemolysis, and anemia: this condition is effectively treated by an enhanced level of fetal hemoglobin (HbF). In spite of extensive studies on pharmacologic induction of HbF synthesis, clinical trials based on HbF reactivation in β-thalassemia produced inconsistent results. Here, we investigated the in vitro response of β-thalassemic erythroid progenitors to kit ligand (KL) in terms of HbF reactivation, stimulation of effective erythropoiesis, and inhibition of apoptosis. In unilineage erythroid cultures of 20 patients with intermedia or major β-thalassemia, addition of KL, alone or combined with dexamethasone (Dex), remarkably stimulated cell proliferation (3-4 logs more than control cultures), while decreasing the percentage of apoptotic and dyserythropoietic cells (<5%). More important, in both thalassemic groups, addition of KL or KL plus Dex induced a marked increase of γ-globin synthesis, thus reaching HbF levels 3-fold higher than in con-trol cultures (eg, from 27% to 75% or 81%, respectively, in β-thalassemia major). These studies indicate that in β-thalassemia, KL, alone or combined with Dex, induces an expansion of effective erythropoiesis and the reactivation of γ-globin genes up to fetal levels and may hence be considered as a potential therapeutic agent for this disease

Iron up-modulates the expression of transferrin receptors during monocyte-macrophage maturation

Abstract We have investigated the effect of iron on the expression of transferrin receptors (TrfRs) and ferritin chains in cultures of human peripheral blood monocytes maturing to macrophages. Monocyte-macrophage maturation is associated with a gradual rise of Trf-binding capacity in the absence of cell proliferation. At all culture times, treatment with ferric ammonium citrate induces a dose-dependent rise of the Trf-binding level as compared with nontreated cells. Scatchard analysis revealed that this phenomenon is due to an increase in receptor number rather than an alteration in ligand-receptor affinity. Biosynthesis experiments indicated that the rise in number of TrfRs is due to an increase of receptor synthesis, which is associated with a sustained elevation of the TrfR RNA level. The up-regulation of TrfR synthesis is specific in that expression of other macrophage membrane proteins is not affected by iron addition. Conversely, addition of an iron chelator induced a slight decrease of TrfR synthesis. The expression of heavy and light ferritin chains at RNA and protein levels was markedly more elevated in cultured macrophages than in fresh monocytes, thus suggesting modulation of ferritin genes at transcriptional or post-transcriptional levels. Addition of iron salts to monocyte-macrophage cultures sharply stimulated ferritin synthesis but only slightly enhanced the level of ferritin RNA, thus indicating a modulation at the translational level. These results suggests that in cultured human monocytes-macrophages, iron up-regulates TrfR expression, thus in sharp contrast to the negative feedback reported in a variety of other cell types. These observations may shed light on the mechanism(s) of iron storage in tissue macrophages under normal conditions and possibly on the pathogenesis of diseases characterized by abnormal iron storage

CAR-T CELL THERAPY FOR FOLLICULAR LYMPHOMAS

Follicular lymphoma is the second most diagnosed lymphoma in Western Europe. Significant advancements have considerably improved the survival of FL patients. However, 10-20% of these patients are refractory to standard treatments, and most of them will relapse. The treatment of follicular lymphoma patients with multiply relapsed or refractory disease represents an area of high-unmet needing new treatments with stronger efficacy. Chimeric antigen receptor (CAR)-T cell therapy targeting B-cell antigens, such as CD19 or CD20, is emerging as an efficacious treatment for R/R follicular lymphoma patients, particularly for those with early relapse and refractory to alkylating agents and to anti-CD20 monoclonal antibodies, resulting in a high rate of durable responses in a high proportion of patients.