Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Indisputable advances in the conventional therapy of chronic myeloid leukemia (CML), like the establishment of interferon-alfa as the standard treatment for first chronic phase patients and the introduction of imatinib-mesylate as a highly active compound in patients failing interferon-alfa treatment or with more advanced disease are challenging allogeneic stem cell transplantation (SCT) as the single treatment modality, which currently offers long-term remissions below the threshold of sensitive molecular methods for the detection of BCR-ABL transcripts. Since stable molecular remissions are thought to be a prerequisite for cure of CML, allogeneic SCT remains the only curative treatment option for younger patients (i.e. beyond the age of 55 years), who have an HLA-matched related or unrelated donor. Nowadays, suitable HLA-matched unrelated donors can be identified for 70% to 75% of caucasian patients lacking an HLA-identical sibling donor, which substantially has promoted the broader application of allogeneic SCT.
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PMID:Allogeneic stem cell transplants in chronic myeloid leukemia. 1261 Oct 74

The understanding of the use of donor lymphocyte infusions (DLI) for graft-versus-leukaemia (GVL) in the treatment of chronic myeloid leukaemia (CML) post haemopoietic stem cell transplant (HSCT) has advanced during the last years. In relapsed leukaemia post-stem cell transplant, DLI can achieve durable remissions in 60-73% patients. Technical improvements in molecular methods of detection of the BCR-ABL transcripts permit the prediction of relapse with increased sensitivity and reproducibility. Use of DLI early at relapse is important since responses to DLI are less likely in the face of bulky or blast-phase disease. Exogenous interleukin-2 may enhance the response to DLI but total cell dose is also relevant to the efficacy of DLI with the effective cell dose (ECD) required being lower in HLA matched unrelated DLI donors compared to siblings. Donor T-lymphocytes target minor histocompatibility (H) antigens and the relative tissue distribution of these may influence the toxicity of DLI, which includes graft-versus-host-disease (GVHD). Modified methods of delivery such as selective deletion of CD8+ cells or escalating cell dosage regimens have reduced the incidence of serious morbidity due to GVHD without compromising the GVL effect mediated by DLI. These approaches have not removed the risk of GVHD entirely and conditional suicide protocols utilising the HSV-tk or fas receptor derived genes are being developed in the clinic. Since significant morbidity and mortality is attributable to the conditioning regimen used prior to HSCT, awareness of the potency of DLI has driven the development of reduced intensity conditioning (RIC) regimens. The purpose of RIC is to enhance tolerisation of the host to the graft while permitting the establishment of donor haemopoiesis. DLI may then be used subsequently to enhance the GVL effect.
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PMID:Donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukaemia. 1269 Nov 39

Antigens implicated in the graft-versus-leukemia (GVL) effect in chronic myeloid leukemia (CML) include WT1, PR1, and BCR-ABL. To detect very low frequencies of these antigen-specific CD8+ T cells, we used quantitative polymerase chain reaction (qPCR) to measure interferon-gamma (IFN-gamma) mRNA production by peptide-pulsed CD8+ T cells from HLA-A*0201+ healthy volunteers and from patients with CML before and after allogeneic stem cell transplantation (SCT). Parallel assays using cytomegalovirus (CMV) pp65 tetramers demonstrated the IFN-gamma copy number to be linearly related to the frequency of tetramer-binding T cells, sensitive to frequencies of 1 responding CD8+ T cell/100 000 CD8+ T cells. Responses to WT1 and PR1 but not BCR-ABL were detected in 10 of 18 healthy donors. Responses to WT1, PR1, or BCR-ABL were observed in 9 of 14 patients with CML before SCT and 5 of 6 after SCT, often to multiple epitopes. Responses were higher in patients with CML compared with healthy donors and highest after SCT. These antigen-specific CD8+ T cells comprised central memory (CD45RO+CD27+CD57-) and effector memory (CD45RO-CD27-CD57+) T cells. In conclusion, leukemia-reactive CD8+ T cells derive from memory T cells and occur at low frequencies in healthy individuals and at higher frequencies in patients with CML. The increased response in patients after SCT suggests a quantitative explanation for the greater effect of allogeneic SCT.
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PMID:Functional leukemia-associated antigen-specific memory CD8+ T cells exist in healthy individuals and in patients with chronic myelogenous leukemia before and after stem cell transplantation. 1507 Jul 13

We report a 39-year-old female patient who underwent HLA-identical sibling allogeneic BMT for CML in accelerated phase. Severe pancytopenia refractory to G-CSF associated with progressive splenomegaly and RBC/platelet transfusion dependency were present from day +60 after BMT. MRD assessed by FISH and RT-PCR multiplex for BCR-ABL rearrangement was negative, and complete chimerism was documented by VNTR on days +100, +180, +360 and 2 years after BMT. Splenectomy was performed on day +225 and pancytopenia resolved but chronic extensive graft-versus-host disease developed, with hepatic cholestasis, diffuse scleroderma and sicca-like syndrome. She was sequentially and progressively treated with different immunosuppressive therapy combinations with no clear benefit. On day +940, she presented with infection over the previously present ulcers on both limbs, which culminated in septic shock and death on day +1041. We conclude that, although splenectomy may reverse poor graft function after allogeneic BMT, hyposplenism may trigger or worsen chronic extensive GVHD leading to increased morbidity and mortality.
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PMID:Refractory chronic GVHD emerging after splenectomy in a marrow transplant recipient with accelerated phase CML. 1285 7

Chronic myelogenous leukemia (CML) is characterized by a t(9;22) translocation resulting in expression of BCR-ABL fusion oncoproteins which are unique to the leukemic cells, necessary for oncogenesis, and potentially immunogenic. We have previously shown that human dendritic cells transduced with an adeno-associated virus vector encoding the fusion region of the b3a2 splice variant (p210(b3a2)) of the BCR-ABL oncoprotein elicit specific T-cell responses in vitro. Two cytotoxic T lymphocyte (CTL) clones generated in this fashion displayed restriction with previously unreported HLA alleles. The first, T1/B9, was CD4(+) and restricted by DRB5*0101 (autologous) or DRB1*1101 (allogeneic). The minimum cytotoxic epitope (MCE) binding to DRB5*0101 for this clone was identified as FKQSSKALQ, overlapping the p210(b3a2) fusion point (boldface). The MCE of DRB1*1101 for this clone differed from DRB5*0101, but also included the fusion point. The clonality of CTL T1/B9 was verified by analyses of TCRalpha/beta chain usage and DNA sequence analyses. To our knowledge, this is the first description of a single clone recognizing both DRB5*0101 and DRB1*1101. The other CTL clone, T1/33, was CD8+ and recognized HLA-B*3501 or B*3503 complexed with an MCE, RPVASDFEP, derived from the c-abl sequence in proximity to the p210(b3a2) fusion point. K562 cells transfected with plasmids encoding HLA-DRA + B5*0101, B*3501, or B*3503 but not controls expressing DRA + DRB1*1501 were lysed by cognate CTL clones, confirming that DRB5*0101 and B*3501/3 could present p210(b3a2) joining region epitopes via endogenous processing. The identification of three additional HLA alleles (DRB5*0101, B*3501, and B*3503) presenting the p210(b3a2) fusion-region antigen will broaden the application of vaccine strategies for targeting CML cells. The findings of single CTL clones cross-recognizing autologous (DRB5*0101 or B*3501) and allogeneic (DRB1*1101 or B*3503) HLA alleles presenting BCR-ABL fusion-region epitopes implies the potential separation of graft-versus-leukemia from graft-versus-host effects.
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PMID:Identification of new MHC-restriction elements for presentation of the p210(BCR-ABL) fusion region to human cytotoxic T lymphocytes. 1456 82

Chronic rejection is the major limitation to long-term allograft survival. HLA class I signaling pathways have been implicated in this process because ligation of class I molecules by anti-HLA antibodies (Ab) initiates intracellular signals in smooth muscle cells (SMC) and endothelial cells (EC) that synergize with growth factor receptors to elicit cell survival and proliferation. Anti-HLA Ab mediate cell proliferation and survival through a focal adhesion kinase dependent pathway that requires the integrity of the actin cytoskeleton. In this study, we investigated the role of Rho and Rho-kinase (ROK) in class I signal transduction. We show that class I ligation results in activation of Rho and increased stress fiber formation. In addition, inhibitors of Rho GTPase and ROK block HLA class I-mediated tyrosyl phosphorylation of paxillin and FAK, central elements of the focal adhesion signaling complex. These results suggest that HLA class I-induced signaling in EC is dependent on Rho GTPase and ROK.
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PMID:HLA class I signal transduction is dependent on Rho GTPase and ROK. 1535 23

Atypical chronic myeloid leukemia (aCML) occurs rarely and is associated with a poor prognosis when treated with conventional chemotherapy. We evaluated the outcome of aCML after allogeneic hematopoietic stem cell transplantation (HSCT). Nine patients were transplanted from HLA-identical siblings (n = 4), HLA-compatible unrelated donors (n = 4) or twin brother (n = 1). Median follow-up was 55 months after transplant (range, 9.1-118.1 months). One patient who was transplanted in advanced disease with bone marrow from his twin brother relapsed 19 months post transplant. This patient was successfully retransplanted from the original donor. All patients remained in complete remission. Analysis of the leukocyte chimerism of peripheral white blood cells and bone marrow buffy coat cells by VNTR-polymerase chain reaction (PCR) and single-nucleotide polymorphism real-time PCR revealed complete chimerism in all patients who had received an allogeneic transplant. One patient suffering from cerebral toxoplasmosis died 9 months post transplant. All other patients were alive at the time of analysis. Our findings suggest that the outcome of allogeneic or syngeneic transplantation in patients with aCML may not be worse than the outcome of transplantation for BCR-ABL-positive CML.
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PMID:Outcome of hematopoietic stem cell transplantation in patients with atypical chronic myeloid leukemia. 1551 46

Activation of STAT1 and the IFN-gamma response are thought to be mediated exclusively through the Y440 motif of the human IFNGR1 receptor subunit. Contrary to this accepted dogma, here it is shown that IFNGR1 with a mutant (Y440F) motif, when stably expressed in IFNGR1-negative human fibroblasts at levels similar to wild type, can sustain a substantial IFN-gamma response. The mutant receptor supports selective induction of IFN-gamma-inducible genes but is notably defective in the CIITA, class II HLA, suppressor of cytokine signaling and antiviral responses. Remarkably, similar selective defects are observed in human fibrosarcoma cells expressing a mutant JAK1. The phenotypes are novel and appear distinct from those observed in response to the inhibition of known additional pathways. Data from different cell types further emphasizes the importance of cellular background in determining the response.
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PMID:Signaling through a mutant IFN-gamma receptor. 1623 89

Chronic myelogenous leukemia is the main diagnosis in case of primitive hyperleucocytosis ou thrombocytosis. The Philadelphia chromosome could be evidenced in the bone marrow by cytogenetic analysis or in the peripheral blood by amplification of the BCR-ABL fusion gene with RT-PCR. A new targeted therapy, imatinib mesylate (Gleevec), inhibits of the dysregulated kinase activity of BCR-ABL. A complete cytogenetic response defined by the absence of Ph+ chromosome in bone marrow is obtained in 85% of cases at the daily dosage of 400 mg. The response is then monitored by quantification of the BCR-ABL transcript. This apparent simple, orally available and well tolerated therapy need to be carefully monitored by real time quantitative PCR in highly specialized laboratories. Allogenic hematopoietic stem cell transplantation remains a curative approach in case of HLA identical donor and is proposed to young patients or in case of imatinib failure. A second generation of BCR-ABL inhibitors is currently in clinical trial.
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PMID:[Diagnosis and treatment of chronic myelogenous leukemia]. 1633 1

The study comprised 37 consecutive patients who underwent transplantation with a Campath-1H in vitro T cell-depleted granulocyte colony-stimulating factor-mobilized peripheral blood stem cell graft from an HLA-identical sibling, followed 24 hours later by an unmanipulated graft. Acute graft-versus-host disease (GVHD) was limited to grade I to II, whereas chronic graft-versus-host disease occurred in 9 patients, mostly (n = 7) with limited disease. Molecular relapses (8 chronic myeloid leukemia [CML] and 1 non-Hodgkin lymphoma) that occurred not earlier than the sixth month after transplantation were treated with donor lymphocyte infusion (DLI), which induced complete remission in all but 1 CML patient with persistent very low BCR-ABL molecular levels. With a median follow-up of 54 months (range, 29-84 months), the actuarial 5-year overall survival, disease-free survival, and transplant-related mortality are 78% (95% confidence interval [CI], 52%-88%), 78% (95% CI, 52%-86%), and 6% (95% CI, 1.5%-32%), respectively. All CML patients are alive and free of disease. The results of this prospective, nonrandomized study show that incomplete T-cell depletion in vitro with Campath-1H (in combination with DLI for molecular relapses in CML) may decrease the incidence of GVHD and transplant-related mortality with no adverse effect on disease-free survival. The described method decreases the number of T cells to an extent that severe GVHD is prevented while relapse is postponed to a time when the patient can be treated with DLI without severe side effects.
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PMID:Can only partial T-cell depletion of the graft before hematopoietic stem cell transplantation mitigate graft-versus-host disease while preserving a graft-versus-leukemia reaction? A prospective phase II study. 1639 74


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