Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The recent identification of somatic mutations such as JAK2V617F that deregulate Janus kinase (JAK)-signal transducer and activator of transcription signaling has spurred development of orally bioavailable small-molecule inhibitors that selectively target JAK2 kinase as an approach to pathogenesis-directed therapy of myeloproliferative disorders (MPD). In pre-clinical studies, these compounds inhibit JAK2V617F-mediated cell growth at nanomolar concentrations, and in vivo therapeutic efficacy has been demonstrated in mouse models of JAK2V617F-induced disease. In addition, ex vivo growth of progenitor cells from MPD patients harboring JAK2V617F or MPLW515L/K mutations is also potently inhibited. JAK2 inhibitors currently in clinical trials can be grouped into those designed to primarily target JAK2 kinase (JAK2-selective) and those originally developed for non-MPD indications, but that nevertheless have significant JAK2-inhibitory activity (non-JAK2 selective). This article discusses the rationale for using JAK2 inhibitors for the treatment of MPD, as well as relevant aspects of clinical trial development for these patients. For instance, which group of MPD patients is appropriate for initial Phase I studies? Should JAK2V617F-negative MPD patients be included in the initial studies? What are the likely consequences of 'off-target' JAK3 and wild-type JAK2 inhibition? How should treatment responses be monitored?
Leukemia 2008 Jan
PMID:JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials. 1788 82

Drosophila has emerged as an important model system to discover and analyze genes controlling hematopoiesis. One regulatory network known to control hemocyte differentiation is the Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) signal-transduction pathway. A constitutive activation mutation of the Janus kinase Hopscotch (hopscotch(Tumorous-lethal); hop(Tum-l)) results in a leukemia-like over-proliferation of hemocytes and copious differentiation of lamellocytes during larval stages. Here we show that the Friend of GATA (FOG) protein U-shaped (Ush) is expressed in circulating and lymph gland hemocytes, where it plays a critical role in controlling blood cell proliferation and differentiation. Our findings demonstrate that a reduction in ush function results in hematopoietic phenotypes strikingly similar to those observed in hop(Tum-l) animals. These include lymph gland hypertrophy, increased circulating hemocyte concentration, and abundant production of lamellocytes. Forced expression of N-terminal truncated versions of Ush likewise leads to larvae with severe hematopoietic anomalies. In contrast, expression of wild-type Ush results in a strong suppression of hop(Tum-l) phenotypes. Taken together, our findings demonstrate that U-shaped acts to control larval hemocyte proliferation and suppress lamellocyte differentiation, likely regulating hematopoietic events downstream of Hop kinase activity. Such functions appear to be facilitated through Ush interaction with the hematopoietic GATA factor Serpent (Srp).
 ...
PMID:The Friend of GATA protein U-shaped functions as a hematopoietic tumor suppressor in Drosophila. 1793 44

Optimal clinical management of patients with primary myelofibrosis and post-essential thrombocythemia/polycythemia vera myelofibrosis is a challenge, given the typically advanced age of presentation and variability of the disease course and prognosis. Current medical therapeutic options have not demonstrated an impact on the disease course, which exceeds the palliation of disease-related extramedullary hematopoiesis and alleviation of cytopenias. In contrast, allogeneic stem cell transplantation (SCT) can lead to 'cure' but is limited due to patient's age or comorbidities. Currently, in patients, who are reasonable candidates, SCT (frequently with a reduced intensity conditioning regimen) is employed for intermediate- to high-risk disease. Current pharmaco-medical therapy is used as a bridge to transplant, or instead of transplant in poor transplant candidates. Pathogenetic insights, especially the discovery of the Janus kinase (JAK)2(V617F) mutation, have ushered in a host of new potential therapeutic agents that may augment the role of medical therapy. Similarly, the boundaries of transplantation continue to alter with strategies that decrease conditioning-related toxicity, improved antimicrobial prophylaxis and decreased graft-versus-host disease. The potential for continued improvements in both medical and transplant therapy suggests that for the immediate future the optimal choices for an individual patient will remain potentially volatile and present complex decisions.
Leukemia 2008 Mar
PMID:Choosing between stem cell therapy and drugs in myelofibrosis. 1818 25

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway mediates signaling by cytokines, which control survival, proliferation and differentiation of several cell types. Constitutive JAK activation leads to persistent activation of STAT transcription factors, and several cancers exhibit constitutive STAT activation, in the absence of JAK or STAT activating mutations. Recently, a unique somatic mutation in JAK2 was identified in a majority of patients with myeloproliferative neoplasms. This mutation, encoding a V617F substitution, promotes JAK2 catalytic activation and cytokine-independent signaling. JAK2 and JAK3 mutations have also been identified in a minority of polycythemia vera and acute megakaryoblastic leukemia patients, and it is predicted that further JAK-STAT mutations will be identified in different cancers. Recent discoveries also suggest that mutated JAK proteins will be potent targets for anti-cancer therapy.
 ...
PMID:Mining for JAK-STAT mutations in cancer. 1829 58

Transcription factors from the family of Signal Transducers and Activators of Transcription (STAT) are activated by numerous cytokines. Two members of this family, STAT5A and STAT5B (collectively called STAT5), have gained prominence in that they are activated by a wide variety of cytokines such as interleukins, erythropoietin, growth hormone, and prolactin. Furthermore, constitutive STAT5 activation is observed in the majority of leukemias and many solid tumors. Inactivation studies in mice as well as human mutations have provided insight into many of STAT5's functions. Disruption of cytokine signaling through STAT5 results in a variety of cell-specific effects, ranging from a defective immune system and impaired erythropoiesis, the complete absence of mammary development during pregnancy, to aberrant liver function. On a molecular level, STAT5 has been linked to cell specification, proliferation, differentiation, and survival. Evidence is growing that the diverse outcomes of STAT5 signaling are not only determined by the expression of specific receptors but also by the interaction of STAT5 with cofactors and the cell-specific activity of members of the SOCS family, which negatively regulate STAT function. In this review, we focus on emerging concepts and challenges in the field of Janus kinase (JAK)-STAT5 signaling. First, we discuss unique functions of STAT5 in three distinct systems: mammary epithelial cells, hepatocytes, and regulatory T cells. Second, we present an example of how STAT5 can achieve cell specificity in hepatocytes through a physical and functional interaction with the glucocorticoid receptor. Third, we focus on the relevance of STAT5 in the development and progression of leukemia. Next, we discuss lessons derived from human mutations and disease. Finally, we address an emerging issue that the interpretation of experiments from STAT5-deficient mice and cells might be compromised as these cells might reroute and reprogram cytokine signals to the "wrong" STATs and thus acquire inappropriate cues. We propose that mice with mutations in various components of the JAK-STAT signaling pathway are living laboratories, which will provide insight into the versatility of signaling hardware and the adaptability of the software.
 ...
PMID:Interpretation of cytokine signaling through the transcription factors STAT5A and STAT5B. 1834 89

Trophoblast cells display a very unique capability: they physiologically invade into the surrounding tissue. This capability is widely associated with tumours, and, indeed, the invasive behaviour of both is rather similar. The imposing difference is that trophoblast cell invasion is temporally and locally controlled in contrast to unlimited tumour invasion. It initiates immediately after embryo implantation into the endometrium. Parallel to tumours, trophoblasts secrete proteases, such as matrix metalloproteinases, which dissolve the extracellular matrix and the surrounding tissue. Thereby, these proteases prepare and allow true invasion of trophoblasts. The invasive capacities of trophoblasts are positively and negatively regulated by numerous cytokines including leukaemia inhibitory factor (LIF), interleukin-6, hepatocyte growth factor, granulocyte macrophage-colony stimulating factor and others. They interact via specific receptors with the trophoblast cells, in which they activate intracellular signalling cascades. These will then induce expression of invasion relevant genes. One of these signalling pathways is the Janus kinase/signal transducers and activators of transcription (STAT) pathway. Especially phosphorylated STAT3 enhances invasiveness of tumours and trophoblast cells, where it is mainly activated by LIF. One of its most efficient physiological antagonists is suppressor of cytokine signalling 3. The balance of these two intracellular molecules seems to be a key regulator of tumour and trophoblast invasion.
 ...
PMID:Trophoblast invasion: the role of intracellular cytokine signalling via signal transducer and activator of transcription 3 (STAT3). 1842 27

The four mammalian Janus kinase (JAK) family members, JAK1, JAK2, JAK3 and TYK2, are non-receptor protein tyrosine kinases (PTKs) that are crucial for cytokine receptor signaling in blood formation and immune responses. Mutations and translocations in the JAK genes leading to constitutively active JAK proteins are associated with a variety of hematopoietic malignancies, including the myeloproliferative disorders (JAK2), acute lymphoblastic leukemia (JAK2), acute myeloid leukemia (JAK2, JAK1), acute megakaryoblastic leukemia (JAK2, JAK3) and T-cell precursor acute lymphoblastic leukemia (JAK1). In contrast, loss-of-function mutations of JAK3 and TYK2 lead to immunodeficiency. The role of JAKs as therapeutic targets is starting to expand, as more insights into their structure and activation mechanisms become available.
 ...
PMID:JAKs in pathology: role of Janus kinases in hematopoietic malignancies and immunodeficiencies. 1868 96

Leukaemia inhibitory factor (LIF) is a member of the IL-6 cytokine family which signals through cognate receptors and activates target genes involved in survival, apoptosis, proliferation, differentiation and suppression of differentiation in different cell types. Binding of LIF to the LIFRalpha/gp130 receptor complex has been shown to activate the Janus kinase-signal transducer and activator of transcription 3 pathway. Here we show that activation of naturally occurring and adaptive regulatory T cells leads to increased LIF expression which is abrogated by cyclic adenosine monophosphate. Furthermore, the LIF receptors gp130 and LIFRalpha are upregulated on the surface of activated T cells and signal transducer and activator of transcription 3 phosphorylation is increased. Interestingly, LIF was not required for suppressive function but rather appeared to have a stimulatory effect on T cells that served to modulate and counteract immunosuppression by regulatory T cells.
 ...
PMID:Human naturally occurring and adaptive regulatory T cells secrete high levels of leukaemia inhibitory factor upon activation. 1878 68

Epigenetic changes provide a frequent mechanism for transcriptional silencing of genes in cancer cells. We previously established that epigenetic mechanisms are important for control of group IIA phospholipase A(2) (PLA2G2A) gene transcription in human DU-145 prostate cells. In this study, we analyzed the involvement of such mechanisms in the regulation of five sPLA(2) isozymes and the M-type receptor of sPLA(2) (sPLA(2)-R) in human leukemic Jurkat cells. These cells constitutively expressed sPLA(2)-IB, sPLA(2)-III, sPLA(2)-X, and sPLA(2)-R but not sPLA(2)-IIA and sPLA(2)-V. Transcription of sPLA(2)-IIA and sPLA(2)-V was, however, detected after exposure of cells to the DNA demethylating agent, 5-aza-2'-deoxycytidine (5-aza-dC). Expression of sPLA(2)-IIA was further enhanced by additional exposure to interferon-gamma and blocked by inhibitors of specificity protein 1, nuclear factor kappaB, and Janus kinase/signal transducer and activator of transcription-dependent pathways. Sequence analysis and methylation-specific polymerase chain reaction of bisulfite-modified genomic DNA revealed two 5'-CpG sites (-111 and -82) in the sPLA(2)-IIA proximal promoter that were demethylated after 5-aza-dC treatment. These sites may be involved in the DNA binding of specificity protein 1 and other transcription factors. Similar findings after treatment of human U937 leukemia cells with 5-aza-dC indicate that this mechanism of PLA2G2A gene silencing is not restricted to Jurkat and DU-145 cells. These data establish that regulation of sPLA(2)-IIA and sPLA(2)-V in Jurkat and other cells involves epigenetic silencing by DNA hypermethylation.
 ...
PMID:Involvement of epigenetic mechanisms in the regulation of secreted phospholipase A2 expressions in Jurkat leukemia cells. 1895 28

Embryonic carcinoma (EC) cells, which are malignant stem cells of teratocarcinoma, have numerous morphological and biochemical properties in common with pluripotent stem cells such as embryonic stem (ES) cells. However, three EC cell lines (F9, P19 and PCC3) show different developmental potential and self-renewal capacity from those of ES cells. All three EC cell lines maintain self-renewal capacity in serum containing medium without Leukemia Inhibitory factor (LIF) or feeder layer, and show limited differentiation capacity into restricted lineage and cell types. To reveal the underlying mechanism of these characteristics, we took the approach of characterizing extrinsic factors derived from EC cells on the self-renewal capacity and pluripotency of mouse ES cells. Here we demonstrate that EC cell lines F9 and P19 produce factor(s) maintaining the undifferentiated state of mouse ES cells via an unidentified signal pathway, while P19 and PCC3 cells produce self-renewal factors of ES cells other than LIF that were able to activate the STAT3 signal; however, inhibition of STAT3 activation with Janus kinase inhibitor shows only partial impairment on the maintenance of the undifferentiated state of ES cells. Thus, these factors present in EC cells-derived conditioned medium may be responsible for the self-renewal capacity of EC and ES cells independently of LIF signaling.
 ...
PMID:Extrinsic factors derived from mouse embryonal carcinoma cell lines maintain pluripotency of mouse embryonic stem cells through a novel signal pathway. 1920 80


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>