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

Four xanthocillins (1-4), including a new compound 4, were isolated from cultured marine fungus Basipetospora sp. as thrombopoietin (TPO) mimics. Compounds 1-4 promoted the proliferation of a TPO-sensitive human leukemia cell line, UT-7/TPO, and UT-7/EPO-mpl, genetically engineered to express c-Mpl, a receptor for TPO in dose-dependent manners. However, the proliferation of UT-7/EPO, a parental cell line of UT-7/EPO-mpl that was devoid of TPO receptor, was not affected by them. Thrombopoietic action of compound 1 was nearly as potent as that of TPO, inducing cell proliferation at a concentration ranging from 1 to 100nM. Compound 1 also induced the phosphorylation of several proteins, including Janus kinase 2 (Jak2), signal transducers, and activators of transcription-3 (STAT3) and STAT5 in the UT-7/EPO-mpl cell line, but not in the UT-7/EPO cell line. These data indicated that xanthocillins are putative agonists for c-Mpl, as their cellular actions were analogous to those of TPO.
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PMID:Xanthocillins as thrombopoietin mimetic small molecules. 1611 72

Adult T cell leukemia is an aggressive and frequently fatal malignancy that expressess constitutively activated growth-signaling pathways in association with deregulated growth and resistance to apoptosis. Curcumin (diferuloylmethane) is a naturally occurring yellow pigment, isolated from the rhizomes of the plant Curcuma longa that has traditionally been used in the treatment of injury and inflammation. But the effect and mechanism of action of curcumin on T cell leukemia is not known. To investigate the antitumor activity of curcumin in T cell leukemia, we examined its effect on constitutive phosphorylation of JAK and STAT proteins, proliferation, and apoptosis in HTLV-I-transformed T cell lines. HTLV-I-transformed T cell leukemia lines, MT-2, HuT-102, and SLB-1, express constitutively phosphorylated JAK3, TYK2, STAT3, and STAT5 signaling proteins. In vitro treatment with curcumin induced a dose-dependent decrease in JAK and STAT phosphorylation resulting in the induction of growth-arrest and apoptosis in T cell leukemia. The induction of growth-arrest and apoptosis in association with the blockade of constitutively active JAK-STAT pathway suggests this be a mechanism by which curcumin induces antitumor activity in T cell leukemia.
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PMID:Curcumin induces growth-arrest and apoptosis in association with the inhibition of constitutively active JAK-STAT pathway in T cell leukemia. 1636 42

The fusion tyrosine kinases (FTKs) are generated by chromosomal translocations creating bipartite proteins in which the kinase is hyperactivated by an adjoining oligomerization domain. Autophosphorylation of the FTK generates a 'signalosome', an ensemble of signalling proteins that transduce signals to downstream pathways. At the earliest stages of oncogenesis, FTKs can mimic mitogenic cytokine signalling pathways involving the GAB-2 adaptor protein and signal transducers and activators of transcription (STAT) factors, generating replicative stress and thereby promoting a mutator phenotype. In parallel, FTKs couple to survival pathways that upregulate prosurvival proteins such as Bcl-xL, so preventing DNA-damage-induced apoptosis. Following transformation, FTKs induce resistance to genotoxic attack by upregulating DNA repair mechanisms such as STAT5-dependent RAD51 transcription. The phenomenon of 'oncogene addiction' reflects the continued requirement of an active FTK 'signalosome' to mediate survival and mitogenic signals involving the PI 3-kinase and mitogen-activated protein stress-activated protein kinase pathways, and the nuclear factor-kappa B, activator protein 1 and STAT transcription factors. The available data so far suggest that FTKs, with some possible exceptions, induce and maintain the transformed state using similar panoplies of signals, a finding with important therapeutic implications. The FTK signalling field has matured to an exciting phase in which rapid advances are facilitating rational drug design.
Leukemia 2006 Apr
PMID:Fusion tyrosine kinase mediated signalling pathways in the transformation of haematopoietic cells. 1648 13

STAT5 (signal transducers and activators of transcription) are suggested to play a role in the pathogenesis of leukaemia and lymphoma; however, their influence on the growth of cutaneous T-cell lymphoma cells is not clear enough. The aim of our study was to analyse the function of STAT5 proteins in the proliferation and apoptosis of selected cutaneous T-cell lymphoma cell lines (HUT 78; PB-1; HUT 102B), using antisense oligodeoxynucleotide (ODN) strategy. RT-PCR and Western blot were applied to analyse the expression of STAT5 after incubation with antisense ODN (AS ODN). The effect of ODN pretreatment on the cell clonogenecity was analysed in methylcellulose cultures. The process of apoptosis was estimated using two different flow cytometry (FACScan) methods: (1) combined Annexin V/propidium iodide staining, (2) the TUNEL method. Perturbation of STAT5 expression reduced the proliferation of the PB-1 cells after a 24-h exposure to antisense ODNs. Prolonged exposure (72 h) decreased the growth of each examined cell line, especially after antisense STAT5A (AS STAT5A) treatment. Incubation with AS STAT5 induced apoptosis in the population of HUT 78 and PB-1 cells. STAT5s may play a significant role in the growth and the process of apoptosis of selected human cutaneous T-cell lymphoma cells.
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PMID:The influence of STAT5 antisense oligodeoxynucleotides on the proliferation and apoptosis of selected human cutaneous T-cell lymphoma cell lines. 1650 15

Previous studies have shown that activation of the signal transducer and activator of transcription 5 (STAT5) plays an essential role in leukemogenesis mediated through constitutive activated protein tyrosine kinases (PTK). Because PIM-1 is a STAT5 target gene, we analyzed the role of the family of PIM serine/threonine kinases (PIM-1 to PIM-3) in PTK-mediated transformation of hematopoietic cells. Ba/F3 cells transformed to growth factor independence by various oncogenic PTKs (TEL/JAK2, TEL/TRKC, TEL/ABL, BCR/ABL, FLT3-ITD, and H4/PDGFbetaR) show abundant expression of PIM-1 and PIM-2. Suppression of PIM-1 activity had a negligible effect on transformation. In contrast, expression of kinase-dead PIM-2 mutant (PIM-2KD) led to a rapid decline of survival in Ba/F3 cells transformed by FLT3-ITD but not by other oncogenic PTKs tested. Coexpression of PIM-1KD and PIM-2KD abrogated growth factor-independent growth of Ba/F3 transformed by several PTKs, including BCR/ABL. Targeted down-regulation of PIM-2 by RNA interference (RNAi) selectively abrogated survival of Ba/F3 cells transformed by various Fms-like tyrosine kinase 3 (FLT3)-activating mutants [internal tandem duplication (ITD) and kinase domain] and attenuated growth of human cell lines containing FLT3 mutations. Interestingly, cells transformed by FLT3 and BCR/ABL mutations that confer resistance to small-molecule tyrosine kinase inhibitors were still sensitive to knockdown of PIM-2, or PIM-1 and PIM-2 by RNAi. Our observations indicate that combined inactivation of PIM-1 and PIM-2 interferes with oncogenic PTKs and suggest that PIMs are alternative therapeutic targets in PTK-mediated leukemia. Targeting the PIM kinase family could provide a new avenue to overcome resistance against small-molecule tyrosine kinase inhibitors.
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PMID:Targeting PIM kinases impairs survival of hematopoietic cells transformed by kinase inhibitor-sensitive and kinase inhibitor-resistant forms of Fms-like tyrosine kinase 3 and BCR/ABL. 1658 10

Breakpoint cluster region/Abelson (BCR/ABL) tyrosine kinase enhances the ability of leukemia cells to infiltrate various organs. We show here that expression of the helix-loop-helix transcription factor Id1 is enhanced by BCR/ABL in a signal transducer and activator of transcription 5 (STAT5)-dependent manner. Enhanced expression of Id1 plays a key role in BCR/ABL-mediated cell invasion. Down-regulation of Id1 in BCR/ABL leukemia cells by the antisense cDNA significantly reduced their invasive capability through the Matrigel membrane and their ability to infiltrate hematopoietic and nonhematopoietic organs resulting in delayed leukemogenesis in mice. The Id1-promoted cell invasiveness was seemingly mediated by matrix metalloproteinase 9 (MMP9). Transactivation of MMP9 promoter in BCR/ABL cells was dependent on Id1 and abrogation of the MMP9 catalytic activity by a metalloproteinase inhibitor or blocking antibody decreased invasive capacity of leukemia cells. These data suggest that BCR/ABL-STAT5-Id1-MMP9 pathway may play a critical role in BCR/ABL-mediated leukemogenesis by enhancing invasiveness of leukemia cells.
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PMID:Id1 transcription inhibitor-matrix metalloproteinase 9 axis enhances invasiveness of the breakpoint cluster region/abelson tyrosine kinase-transformed leukemia cells. 1661 31

Hematopoietic stem cells in myeloproliferative diseases mostly retain the potential to differentiate but are characterized by hyper-responsiveness to growth factors, as well as partial factor-independent growth. The V617F activating point mutation in Jak2 has recently been associated with myeloproliferative disorders. Using various cell line models, mechanisms that contribute to Jak2V617-mediated signaling were investigated. Treatment of the Jak2V617F mutant-expressing erythroid leukemia cell line HEL with a small molecule Jak2 inhibitor was associated with a dose-dependent G(1) cell cycle arrest. This inhibition correlated with decreased expression of cyclin D2 and increased expression of the cell cycle inhibitor p27(Kip). Inhibition of Jak2V617F with a Jak2-targeted small interfering RNA approach resulted in a similar phenotype. Mechanisms leading to altered p27(Kip) and cyclin D2 likely involve inhibition of STAT5, a major target of Jak2 in hematopoietic cells, because a constitutively active form of STAT5 reduced p27(Kip) and increased cyclin D2 expression. Jak2V617F and constitutively active STAT5 also induced high levels of reactive oxygen species, which are sufficient to promote G(1)/S phase transition. In contrast, treatment of HEL cells with the antioxidant N-acetylcysteine decreased cell growth or expression of cyclin D2 and increased expression of p27(Kip). Similar results were obtained in BaF3 cells transfected with Jak2V617F, but these cells required coexpression of the erythropoietin receptor for optimal signaling. These results suggest that regulation of cyclin D2 and p27(Kip) in combination with redox-dependent processes promotes G(1)/S phase transition downstream of Jak2V617F/STAT5 and therefore hint at potential novel targets for drug development that may aid traditional therapy.
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PMID:Activated Jak2 with the V617F point mutation promotes G1/S phase transition. 1663 70

Most human leukemia cells are shown to express growth hormone receptor (GHR) and some of them proliferate in response to GH. We demonstrate that Src contributes to GHR-mediated signal transduction via STAT5 activation in F-36P human leukemia cells stimulated with GH. The tyrosine phosphorylation levels of GHR and STAT5 induced by GH decreased in the presence of PP2 Src kinase inhibitor. When GHR and wild-type Src were co-expressed in COS7 cells, GHR was markedly tyrosine phosphorylated as well as when Jak2 was co-expressed with GHR, but not when kinase-inactive Src co-expressed. The treatment of F-36P cells with the antisense src oligonucleotides, which selectively decreased the Src expression, reduced the rhGH-induced tyrosine phosphorylation of the STAT5 activation sites.
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PMID:Src transduces signaling via growth hormone (GH)-activated GH receptor (GHR) tyrosine-phosphorylating GHR and STAT5 in human leukemia cells. 1665 Aug 92

The receptor tyrosine kinase Flt3 plays an important role in proliferation and survival of hematopoietic cells. Flt3 is the most frequently mutated gene (20-30%) in cases of acutemyeloid leukemia (AML). The majority of Flt3 mutations are internal tandem duplications (ITD) in the juxtamembrane domain of Flt3 receptor. This mutation results in the constitutive activation of STAT5 and Ras/mitogen-activated protein kinase pathways, leading to the aberrant growth of AML cells. In this study, to better understand the mechanisms of Flt3-ITD to the downstream pathways, a high-throughput immunoblotting protein array system was employed. As a result, c-Jun and c-Raf were markedly induced, suggesting that these factors are functional downstream targets of Flt3-ITD.
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PMID:Identification of Flt3 internal tandem duplications downstream targets by high-throughput immunoblotting protein array system. 1683 37

An activating point mutation in Janus kinase 2 (JAK2 V617F) was recently identified in myelofibrosis with myeloid metaplasia (MMM). To further elucidate the pathogenic significance, we examined the JAK2 mutation burden, phosphorylation of JAK2 substrates and neutrophil apoptotic resistance. Immunoblotting revealed phosphorylation of signal transducer and activator of transcription-3 (STAT3) in all four JAK2 with high V617F mutant allele burden and seven of eight with intermediate mutant allele burden, but only one of eight with wild-type JAK2 (P<0.001). In contrast, STAT5 phosphorylation was undetectable in patient MMM neutrophils; and phosphorylation of Akt and extracellular signal-regulated kinases (ERKs) failed to correlate with JAK2 mutation status. Apoptosis was lower in MMM neutrophils (median 41% apoptotic cells, n=50) compared to controls (median 66%, n=9) or other myeloproliferative disorder patients (median 53%, n=11; P=0.002). Apoptotic resistance in MMM correlated with anemia (P=0.01) and the JAK2-V617F (P=0.01). Indeed, apoptotic resistance was greatest in MMM neutrophils with high mutant allele burden (median 22% apoptosis, n=5) than with intermediate burden (median 39%, n=23) or wild-type JAK2 (median 47%, n=22; P=0.008). These results suggest that mutant JAK2 contributes to MMM pathogenesis by constitutively phosphorylating STAT3 and diminishing myeloid cell apoptosis.
Leukemia 2006 Oct
PMID:Janus kinase 2 (V617F) mutation status, signal transducer and activator of transcription-3 phosphorylation and impaired neutrophil apoptosis in myelofibrosis with myeloid metaplasia. 1687 Dec 75


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