Realization of the T Lineage Program Involves GATA-3 Induction of Bcl11b and Repression of Cdkn2b Expression.

The zinc-finger transcription factor GATA-3 plays a crucial role during early T cell development and also dictates later T cell differentiation outcomes. However, its role and collaboration with the Notch signaling pathway in the induction of T lineage specification and commitment have not been fully elucidated. We show that GATA-3 deficiency in mouse hematopoietic progenitors results in an early block in T cell development despite the presence of Notch signals, with a failure to upregulate Bcl11b expression, leading to a diversion along a myeloid, but not a B cell, lineage fate.

Grb2 regulates the proliferation of hematopoietic stem and progenitors cells.

Although Hematopoietic Stem and Progenitor Cell (HSPC) proliferation, survival and expansion have been shown to be supported by the cooperative action of different cytokines, little is known about the intracellular signaling pathways that are activated by cytokines upon binding to their receptors. Our study showed that Growth factor receptor-bound protein 2 (Grb2) mRNAs are preferentially expressed in HSC compared to progenitors and differentiated cells of the myeloid and erythroid lineages. Conditional deletion of Grb2 induced a rapid decline of erythroid and myeloid progenitors and a progressive decline of HSC numbers in steady state conditions.

Targeting eIF5A Hypusination Prevents Anoxic Cell Death through Mitochondrial Silencing and Improves Kidney Transplant Outcome.

The eukaryotic initiation factor 5A (eIF5A), which is highly conserved throughout evolution, has the unique characteristic of post-translational activation through hypusination. This modification is catalyzed by two enzymatic steps involving deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). Notably, eIF5A may be involved in regulating the lifespan of during long-term hypoxia.

CDK6 levels regulate quiescence exit in human hematopoietic stem cells.

Regulated blood production is achieved through the hierarchical organization of dormant hematopoietic stem cell (HSC) subsets that differ in self-renewal potential and division frequency, with long-term (LT)-HSCs dividing the least. The molecular mechanisms underlying this variability in HSC division kinetics are unknown. We report here that quiescence exit kinetics are differentially regulated within human HSC subsets through the expression level of CDK6.

Lnk adaptor suppresses radiation resistance and radiation-induced B-cell malignancies by inhibiting IL-11 signaling.

The Lnk (Sh2b3) adaptor protein dampens the response of hematopoietic stem cells and progenitors (HSPCs) to a variety of cytokines by inhibiting JAK2 signaling. As a consequence, Lnk(-/-) mice develop hematopoietic hyperplasia, which progresses to a phenotype resembling the nonacute phase of myeloproliferative neoplasm. In addition, Lnk mutations have been identified in human myeloproliferative neoplasms and acute leukemia.

Self-renewal as a therapeutic target in human colorectal cancer.

Tumor recurrence following treatment remains a major clinical challenge. Evidence from xenograft models and human trials indicates selective enrichment of cancer-initiating cells (CICs) in tumors that survive therapy. Together with recent reports showing that CIC gene signatures influence patient survival, these studies predict that targeting self-renewal, the key 'stemness' property unique to CICs, may represent a new paradigm in cancer therapy.

GATA-3 regulates the self-renewal of long-term hematopoietic stem cells.

The transcription factor GATA-3 is expressed and required for differentiation and function throughout the T lymphocyte lineage. Despite evidence it may also be expressed in multipotent hematopoietic stem cells (HSCs), any role for GATA-3 in these cells has remained unclear. Here we found GATA-3 was in the cytoplasm in quiescent long-term stem cells from steady-state bone marrow but relocated to the nucleus when HSCs cycled.

Neurokinin-1 receptor signalling impacts bone marrow repopulation efficiency.

Tachykinins are a large group of neuropeptides with both central and peripheral activity. Despite the increasing number of studies reporting a growth supportive effect of tachykinin peptides in various in vitro stem cell systems, it remains unclear whether these findings are applicable in vivo. To determine how neurokinin-1 receptor (NK-1R) deficient hematopoietic stem cells would behave in a normal in vivo environment, we tested their reconstitution efficiency using competitive bone marrow repopulation assays.

Hypoxia modifies the feeding preferences of Drosophila. Consequences for diet dependent hypoxic survival.

Background: Recent attention has been given to the relationships between diet, longevity, aging and resistance to various forms of stress. Flies do not simply ingest calories. They sense different concentrations of carbohydrate and protein macronutrients and they modify their feeding behavior in response to changes in dietary conditions.

Intermediate-term hematopoietic stem cells with extended but time-limited reconstitution potential.

Sustained blood cell production depends on divisions by hematopoietic stem cells (HSCs) that yield both differentiating progeny as well as new HSCs via self-renewal. Differentiating progeny remain capable of self-renewal, but only HSCs sustain self-renewal through successive divisions securely enough to maintain clones that persist life-long. Until recently, the first identified next stage consisted of "short-term" reconstituting cells able to sustain clones of differentiating cells for only 4-6 weeks.

Food presentation modifies longevity and the beneficial action of dietary restriction in Drosophila.

Recent studies have indicated that flies respond to dilute food solutions by compensatory feeding. The existence of compensation mechanisms calls for a reconsideration of the relationships between diet, feeding behaviour and longevity. This study shows that flies fed on liquid diets, sense sucrose and yeast nutrients and adapt to changes in the quantity and presentation of the two nutrients.

Strong dietary restrictions protect Drosophila against anoxia/reoxygenation injuries.

Background: Reoxygenation of ischemic tissues is a major factor that determines the severity of cardiovascular diseases. This paper describes the consequences of anoxia/reoxygenation (A/R) stresses on Drosophila, a useful, anoxia tolerant, model organism.

Methodology/principal Findings: Newly emerged adult male flies were exposed to anoxic conditions (<1% O2) for 1 to 6 hours, reoxygenated and their survival was monitored.

NF-kappaB inhibition triggers death of imatinib-sensitive and imatinib-resistant chronic myeloid leukemia cells including T315I Bcr-Abl mutants.

The Bcr-Abl inhibitor imatinib is the current first-line therapy for all newly diagnosed chronic myeloid leukemia (CML). Nevertheless, resistance to imatinib emerges as CML progresses to an acute deadly phase implying that physiopathologically relevant cellular targets should be validated to develop alternative therapeutic strategies. The NF-kappaB transcription factor that exerts pro-survival actions is found abnormally active in numerous hematologic malignancies.

Identification of gene 3' ends by automated EST cluster analysis.

The properties and biology of mRNA transcripts can be affected profoundly by the choice of alternative polyadenylation sites, making definition of the 3' ends of transcripts essential for understanding their regulation. Here we show that 22-52% of sequences in commonly used human and murine "full-length" transcript databases may not currently end at bona fide polyadenylation sites. To identify probable transcript termini over the entire murine and human genomes, we analyzed the EST databases for positional clustering of EST ends.

The role of polyamines in protein-dependent hypoxic tolerance of Drosophila.

Background: Chronic hypoxia is a major component of ischemic diseases such as stroke or myocardial infarction. Drosophila is more tolerant to hypoxia than most mammalian species. It is considered as a useful model organism to identify new mechanisms of hypoxic tolerance.

Plasticity of the responses to chronic hypoxia and dietary restriction in an aged organism: evidence from the Drosophila model.

Major cardiovascular diseases arise as consequences of a reduced blood flow to oxygen consuming organs such as the brain and the heart. Their incidence and consequences increase with ageing and inappropriate nutrition conditions. In this study we compared the responses of young (1 day old) or aged (1 month old) Drosophila to dietary restriction and chronic hypoxia.

Diet dependent longevity and hypoxic tolerance of adult Drosophila melanogaster.

Relationships between nutrition and longevity are of growing interest. Here we analysed the influences of dietary restriction on the survival of Drosophila exposed to atmospheric oxygen or to chronic hypoxia. Dietary restriction was achieved by food dilution, by sucrose restriction or by yeast restriction.

Neurological and functional recovery in human stroke are associated with peripheral blood CD34+ cell mobilization.

Background: A spontaneous mobilization of Peripheral Blood-Mononuclear CD34+ Cells (PB-MNC-CD34+) has recently been reported in human myocardial infarction and found to be related to improved heart function and survival. However, nothing is known regarding a possible relation between PB-MNC-CD34+ mobilization and neurological recovery in human acute cerebral ischemia.

Methods And Results: PB-MNC-CD34+ were determined daily after an acute cerebral ischemic attack for 14 days in 25 patients with acute ischemic stroke and compared with controls.

A low protein diet increases the hypoxic tolerance in Drosophila.

Dietary restriction is well known to increase the life span of a variety of organisms from yeast to mammals, but the relationships between nutrition and the hypoxic tolerance have not yet been considered. Hypoxia is a major cause of cell death in myocardial infarction and stroke. Here we forced hypoxia-related death by exposing one-day-old male Drosophila to chronic hypoxia (5% O(2)) and analysed their survival.

Analysis of the hypoxia-sensing pathway in Drosophila melanogaster.

The mechanism by which hypoxia induces gene transcription involves the inhibition of HIF-1alpha (hypoxia-inducible factor-1 alpha subunit) PHD (prolyl hydroxylase) activity, which prevents the VHL (von Hippel-Lindau)-dependent targeting of HIF-1alpha to the ubiquitin/proteasome pathway. HIF-1alpha thus accumulates and promotes gene transcription. In the present study, first we provide direct biochemical evidence for the presence of a conserved hypoxic signalling pathway in Drosophila melanogaster.

Constitutive activation of STAT proteins in the HDLM-2 and L540 Hodgkin lymphoma-derived cell lines supports cell survival.

Survival and proliferation of Hodgkin lymphoma (HL) cells are influenced by many cytokines produced by different cell types in the lymph node microenvironment. STAT, family of transcription factors, are key mediators of cytokine signaling and their perturbation contributes to various human diseases. Electrophoretic mobility shift and phosphoprotein immunoblotting analyses were used to study STAT activation in HL cell lines.

Targeting NF-kappaB activation via pharmacologic inhibition of IKK2-induced apoptosis of human acute myeloid leukemia cells.

Acute myeloid leukemia (AML) cells are characterized by a constitutive and abnormal activation of the nuclear factor-kappaB (NF-kappaB) transcription factor. This study, conducted in vitro on 18 patients, shows that targeting the IKB kinase 2 (IKK2) kinase with the specific pharmacologic inhibitor AS602868 to block NF-kappaB activation led to apoptosis of human primary AML cells. Moreover, AS602868 potentiated the apoptotic response induced by the current chemotherapeutic drugs doxorubicin, cytarabine, or etoposide (VP16).

Monitoring NF-kappa B transactivation potential via real-time PCR quantification of I kappa B-alpha gene expression.

Background: Nuclear factor-kappa B (NF-kappa B) is an important transcription factor involved in the regulation of immune responses as well as in cell proliferation and survival. An abnormal and constitutive activation of NF-kappa B is observed in many pathological states as diverse as inflammation, neurological diseases, and cancer.

Methods And Results: Termination of NF-kappa B transcription is mediated through the NF-kappa B-dependent synthesis of the I kappa B-alpha inhibitory subunit.