Posted by rob on February 20, 2006 under Uncategorized | 
Protein tyrosine phosphatase 1B (PTP-1B) is a ubiquitously expressed cytosolic phosphatase with the ability to dephosphorylate JAK2 and TYK2, and thereby down-regulate cytokine receptor signaling. Furthermore, PTP-1B levels are up-regulated in certain chronic myelogenous leukemia patients, which points to a potential role for PTP-1B in myeloid development. The results presented here show that the absence of PTP-1B affects murine myelopoiesis by modifying the ratio of monocytes to granulocytes in vivo. This bias toward monocytic development is at least in part due to a decreased threshold of response to CSF-1, because the PTP-1B -/- bone marrow presents no abnormalities at the granulocyte-monocyte progenitor level but produces significantly more monocytic colonies in the presence of CSF-1. This phenomenon is not due to an increase in receptor levels but rather to enhanced phosphorylation of the activation loop tyrosine. PTP-1B -/- cells display increased inflammatory activity in vitro and in vivo through the constitutive up-regulation of activation markers as well as increased sensitivity to endotoxin. Collectively, our data indicate that PTP-1B is an important modulator of myeloid differentiation and macrophage activation in vivo and provide a demonstration of a physiological role for PTP-1B in immune regulation.
Protein tyrosine phosphatase 1B negatively regulates macrophage development through CSF-1 signaling.
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Tumour formations arise as a consequence of alterations in the control of cell proliferation as well as with disorders in interactions between cells and their environment that result in invasion and metastasis. Recent advances in understanding the genetic basis of malignant diseases have been dominated by research in colorectal cancer. Genetic alterations of several proto-oncogenes and tumor-suppressor genes (e.g. APC/MCC, RAS, DCC, p53 mutations and/or allelic losses, hyperexpression of c-MYC and RB genes), as well as other genomic alterations, appear at characteristic stages of tumor development and are observed in most neoplasms. Generally, the normal cell has multiple independent mechanisms that regulate its growth and differentiation potential, and several separate events would, therefore, be needed to override these control mechanisms, as well as induce the other aspects of the transformed phenotype, like metastasis. These signals may be either positive or negative, and the acquisition of tumorigenicity results from genetic changes that affect these control points following a multistep mode. Statistics of the frequency of cancer incidence with age in humans indicate that for the genesis of e.g. lung carcinoma, five or six steps are required. Other types of cancers, such as leukemias and sarcomas, probably require quite a different number of rate-limiting changes. One of the best characterized tumours to provide a genetic model is colorectal tumorigenesis. Mutations implicated in breast cancer tumorigenicity are also studied and used as a genetic model in the literature worldwide. Finally, activation of c-abl in chronic myelogenous leukaemia (CML) and acute lymphoblastic leukaemia could also be presented as an example, which provides probably the strongest evidence for the role of proto-oncogenes in human malignancy process.
Genetic models of human cancer as a multistep process. Paradigm models of colorectal cancer, breast cancer, and chronic myelogenous and acute lymphoblastic leukaemia.
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Kinases are believed to play a crucial role in the expression and activation of inflammatory mediators in the airway, in T-cell function and airway remodelling. Important kinases such as Inhibitor of kappaB kinase (IKK)2, mitogen activated protein (MAP) kinases and phsopho-inositol (PI)3 kinase regulate inflammation either through activation of pro-inflammatory transcription factors such as activating protein-1 (AP-1) and nuclear factor kappaB (NF-kappaB), which are activated in airway disease, or through regulation of mRNA half-life. Selective kinase inhibitors have been developed which reduce inflammation and some characteristics of disease in animal models. Targeting specific kinases that are overexpressed or over active in disease should allow for selective treatment of respiratory diseases. Interest in this area has intensified due to the success of the specific Abelson murine leukaemia viral oncogene (Abl) kinase inhibitor imatinib mesylate (Gleevec) in the treatment of chronic myelogenous leukaemia. Encouraging data from animal models and primary cells and early Phase I and II studies in other diseases suggest that inhibitors of p38 MAP kinase and IKK2 may prove to be useful novel therapies in the treatment of severe asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis and other inflammatory airway diseases.
Kinase inhibitors and airway inflammation.
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OBJECTIVE: To study the effect of co-expressing M-bcr/abl and m-bcr/abl fusion gene transcripts on the clinical features of the patients with chronic myelogenous leukemia (CML) at diagnosis. METHODS: m-bcr/abl fusion gene transcripts were detected by nested PCR. RESULTS: The percentage of the CML patients who co-expressed M-bcr/abl and m-bcr/abl was 51.4% at diagnosis. Comparison of the patients who co-expressed and those who expressed M-bcr/abl alone showed there was no difference in their hemoglobin concentrations, WBC counts, neutrophilic alkaline phosphatase (NAP) stains, Ph chromosomes and hepatosplenomegaly; however, significant difference in platelet count was seen. In the patients with b3a2 who co-expressed m-bcr/abl, an increased platelet count was noted, compared with that of patients with M-bcr/abl alone. But in patients with b2a2, the two groups showed no difference in all clinical features. Two patients had priapism, their m-bcr/abl being negative. CONCLUSIONS: CML patients who co-expressed b3a2 and m-bcr/abl showed a tendency to have an increased platelet count at diagnosis. Co-expressing m-bcr/abl has no the effect on the clinical features of CML patients with b2a2.
[Effect of co-expressing M-bcr/abl and m-bcr/abl fusion gene transcripts on the clinical features of patients with chronic myelogenous leukemia at diagnosis]
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The effects of a novel kind of nitrogen heterocycle compound, which was synthesized in our laboratory previously, on human chronic myelogenous leukemia K562 cells were investigated. The morphological changes were observed by Acridine orange (AO) staining. The screened results through DNA fragmentation and the Annexin V-FITC/PI staining assay showed that compound 8 blocked cell cycles at G(1) phase which led to apoptosis. The increase of caspase-3, 8, and 9 was detected, indicating that both of death-receptor and mitochondria-pathways were activated. Compound 8 induced a biphasic alteration in mitochondrial membrane potential of K562 cells. A dramatic elevation of Ca(2+) was also observed. In addition, a transient increase of ROS was also involved in the process. This study showed that compound 8 might be a potential chemopreventive agent for chronic myelogenous leukemia. It would guide our future work to synthesize more compounds derived from compound 8, which might have better effect, and to determine the target protein. Moreover, it might also provide a background mechanism for the introduction of this new type of promising therapeutic agent.
A novel kind of nitrogen heterocycle compound induces apoptosis of human chronic myelogenous leukemia K562 cells.
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BACKGROUND: Double pathology is uncommon. The diagnostic effort must be directed toward uncovering a disorder that can explain all the findings in a given patient. However, exceptions occur, notably in the sphere of infectious disorders. This is particularly true in the context of multiple infections in immunocompromised patients. CASE: Fine needle aspiration was performed on 2 lymph nodes in a 22-year-old male. Extramedullary hematopoiesis was seen in 1, while the other showed acellular necrosis with acid-fast bacilli. The hematologic workup revealed chronic myelogenous leukemia. CONCLUSION: Extramedullary hematopoiesis can be a cytologic clue to hematologic disorders. A search for an additional infectious disease may be in order.
Concurrent chronic myelogenous leukemia and turberculosis lymphadenitis: a case report.
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Rea D,
Legros L,
Raffoux E,
Thomas X,
Turlure P,
Maury S,
Dupriez B,
Pigneux A,
Choufi B,
Reman O,
Stéphane D,
Royer B,
Vigier M,
Ojeda-Uribe M,
Recher C,
Dombret H,
Huguet F,
Rousselot P
Imatinib combined with high-dose chemotherapy is now becoming the gold standard for treatment of Philadelphia chromosome-positive acute leukemias. However, in all studies imatinib dosage was tapered to 400-600 mg per day. We decided to initiate a clinical trial to evaluate an opposite strategy based on high-dose imatinib (800 mg per day) combined with a less intensive chemotherapeutic regimen (vincristine and dexamethasone), which we called the DIV induction regimen. Thirty-one patients (18 relapsing or refractory Ph+ acute lymphoblastic leukemias and 13 lymphoid blast crisis chronic myelogenous leukemias) were enrolled. Complete remission (CR) was obtained in 28 out of 30 assessable patients. The median bcr-abl/abl ratio after the induction course was 0.1%. Median time to neutrophil recovery was 21 days. Fungus infections were observed in six patients out of 31 and possibly related to dexamethasone. Neuropathy due to vincristine was noted in 14 cases. Nine out of 19 patients under 55 years received allogenic stem cell transplantation after a median time of 78 days post-CR. Patients older than 55 years experienced a 90% CR rate without additional toxicities, suggesting the DIV regimen may also be proposed as a front line therapy in older patients.Leukemia advance online publication, 26 January 2006; (2006) doi:10.1038/sj.leu.2404115.
High-dose imatinib mesylate combined with vincristine and dexamethasone (DIV regimen) as induction therapy in patients with resistant Philadelphia-positive acute lymphoblastic leukemia and lymphoid blast crisis of chronic myeloid leukemia.
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Yang H,
Eaves C,
de Lima M,
Lee MS,
Champlin RE,
McMannis JD,
Robinson SN,
Niu T,
Decker WK,
Xing D,
Ng J,
Li S,
Yao X,
Eaves AC,
Jones R,
Andersson BS,
Shpall EJ
Imatinib-refractory chronic myelogenous leukemia (CML) patients can experience long-term disease-free survival with myeloablative therapy and allogeneic hematopoietic cell transplantation; however, associated complications carry a significant risk of mortality. Transplantation of autologous hematopoietic cells has a reduced risk of complications, but residual tumor cells in the autograft may contribute to relapse. Development of methods for purging tumor cells that do not compromise the engraftment potential of the normal hematopoietic cells in the autograft has been a long-standing goal. Since primitive CML cells differentiate more rapidly in vitro than their normal counterparts and are also preferentially killed by mafosfamide and imatinib, we examined the purging effectiveness on CD34(+) CML cells using a strategy that combines a brief exposure to imatinib (0.5-1.0 muM for 72 h) and then mafosfamide (30-90 mug/ml for 30 min) followed by 2 weeks in culture with cytokines (100 ng/ml each of stem cell factor, granulocyte colony-stimulating factor and thrombopoietin). Treatment with 1.0 muM imatinib, 60 mug/ml mafosfamide and 14 days of culture with cytokines eliminated BCR-ABL(+) cells from chronic phase CML patient aphereses, while preserving normal progenitors. This novel purging strategy may offer a new approach to improving the effectiveness of autologous transplantation in imatinib-refractory CML patients.Bone Marrow Transplantation advance online publication, 23 January 2006; doi:10.1038/sj.bmt.1705284.
A novel triple purge strategy for eliminating chronic myelogenous leukemia (CML) cells from autografts.
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Imatinib mesylate has become the gold standard front-line treatment of chronic myelogenous leukemia through its ability to inhibit ABL tyrosine kinase. Resistance to this inhibition may occur. We investigated the role of the K247R polymorphism in persistent sensitivity.
The role of the K247R substitution in the ABL tyrosine kinase domain in sensitivity to imatinib.
