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)

Manipulation of autologous bone marrow cells (BM) for transplantation in chronic myeloid leukemia (CML) to enrich for normal cells is a novel approach that may improve survival for patients not suitable for allogeneic transplantation. Limitations of this technique include the reported low frequency of normal stem cells in CML and the difficulties in obtaining sufficient BM for manipulation. To address these problems we compared the apheresis product with the diagnostic bone marrow at diagnosis as a source of primitive BCR/ABL-negative progenitors. We analyzed the CD34+ HLA-DR- and CD34+CD38(-) populations in five CML patients to evaluate the frequency of BCR-ABL-negative progenitors and pre-progenitors in these populations. Progenitor analysis was performed by RT-PCR of individual hemopoietic colonies from a standard CFU-GM assay. Analysis of pre-progenitors involved RT-PCR of secondary colonies derived from a stroma-free pre-CFU assay. Our results show variable levels of BCR-ABL-negative progenitors in the 34+DR- population but very low levels of BCR-ABL-negative progenitors in the 34+38- population in blood. Analysis of pre-progenitors from the 34+DR- fraction of peripheral blood (PB) and BM showed 80-100% and 85-100% of colonies were BCR-ABL negative at days 14 and 28, respectively. Analysis of pre-progenitors from the 34+38- fraction of PB and BM showed 23-100% and 42-100% of colonies were BCR-ABL negative at days 14 and 28, respectively. In summary, pre-progenitors from the 34+DR- and 34+38- populations are predominantly BCR-ABL negative in both marrow and blood at diagnosis. Apheresis product collected at diagnosis is a more abundant sources of BCR-ABL-negative pre-progenitors than BM. Thus, apheresis product could potentially be utilized as a source of BCR-ABL-negative stem cells in CML.
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PMID:Peripheral blood is a source of BCR-ABL-negative pre-progenitors in early chronic phase chronic myeloid leukemia. 909 99

Philadelphia chromosome-positive (Ph+) hemopoietic cells predominate in patients with chronic myeloid leukemia (CML) in chronic phase, but some Ph presumably normal stem cells persist in most patients. Ph cells are relatively frequent, compared to mature cell populations, in primitive hemopoietic cell populations from CML patients. We have purified CD34+ cells from chronic phase CML blood and separated them into two fractions on the basis of adherence or non-adherence to tissue culture plastic. We also separated CD34+ CML cell populations into HLA-DR(hi) and HLA-DR(lo) fractions and CD38(hi) and CD38(lo) fractions by flow cytometry. The CD34+ cells that adhered to plastic were predominantly CD33-, CD38- and HLA(-)-DR; cells with these phenotypic properties were significantly rarer in the CD34+ non-adherent cell population (P = 0.008-0.02). Expression of p210 BCR/ABL mRNA by adherent, non-adherent, HLA-DR(hi) and HLA-DR(lo)CD34+ cell subpopulations was demonstrated by RT-PCR. Using fluorescence in situ hybridization (FISH) in conjunction with BCR and ABL probes we detected Ph+ and Ph- cells in both adherent and non-adherent CD34+ cell fractions of 15/15 patients studied and in the HLA-DR(lo) or CD38(lo) sorted CD34+ cell fractions. The concentration of Ph- cells in the adherent CD34+ cell fraction was three-fold higher than in the non-adherent fraction (P = 0.001). Ph- adherent cells were detected in untreated CML patients and as late as 6 years after diagnosis of CML in patients treated with hydroxyurea (HU) or interferon-alpha (IFN-alpha). We conclude that whilst appreciable numbers of Ph- primitive hemopoietic progenitors are present in the circulation in untreated patients and also in treated patients in late chronic phase, the majority of cells expressing CD34 but not CD33, CD38 or HLA-DR antigens, are part of the CML clone.
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PMID:BCR/ABL-negative progenitors are enriched in the adherent fraction of CD34+ cells circulating in the blood of chronic phase chronic myeloid leukemia patients. 930 2

We have used a human salivary gland cell line (HSG) as a possible in vitro model to evaluate the effects of IFN-gamma on human salivary gland epithelium (Wu et al., 1994, 1996, 1997). In the present study, we examined the JAK-STAT signal-transduction pathway in IFN-gamma-treated HSG cells. We demonstrate that JAK2 and Stat1 are phosphorylated at tyrosine residues in a time- and concentration-dependent manner following exposure to IFN-gamma. In addition, we show that activation of this signalling pathway is decreased by the addition of a blocking antibody to the IFN-gamma receptor. The same maneuver is also able to reduce by approximately 50-70% the surface expression of two IFN-gamma-induced immunoregulatory molecules: HLA-DR and ICAM-1. These results demonstrate that the JAK2 and Stat1 signalling pathway is active in salivary-derived epithelial cells and may contribute to their immunopathologic destruction.
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PMID:Interferon-gamma-induced JAK2 and STAT1 signalling in a human salivary gland cell line. 932 55

A large number of continuous human leukemia cell lines have been established over the last three decades. Clearly, leukemia cell lines have become important research tools. Here, we have summarized the immunological, molecular and standard cytogenetic features of a panel of well characterized B cell precursor (BCP)-leukemia cell lines which were derived from patients with acute lymphoblastic/undifferentiated leukemia (ALL/AUL) or chronic myeloid leukemia (CML) in blast crisis. Following the recently proposed immunological EGIL classification, we assigned our panel of 27 BCP-cell lines to one of the following categories: B-I pro-B cell line; B-II common-B cell line; and B-III pre-B cell line. All cell lines express general B-lineage associated surface markers (HLA-DR, CD22, CD79a) being negative for surface immunoglobulin (Ig); the differences between the subgroups reside in expression of CD10 and cytoplasmic Ig. Several BCP-cell lines show the myelomonocytic cell-associated markers CD13 and/or CD33. These immunologically 'biphenotypic' BCP-cell lines are generally TdT+ CD10+ CD13+ CD19+ CD22+ CD34+ and carry the Philadelphia (Ph) translocation. The BCP-cell lines display surface receptors for interferon-gamma (CD119), interleukin-7 (CD127) and FLT-3 ligand (CD135). All BCP-cell lines examined have complex numerical and structural chromosomal alterations including translocations commonly seen in BCP-ALL such as t(4;11), t(9;22), t(11;19), t(12;21), and t(17;19) involving the fusion genes MLL-AF4, BCR-ABL, ENL-MLL, TEL/ETV6-AML1 and E2A-HLF, respectively. Besides the expected rearrangement of the Ig heavy chain receptor gene, several cell lines also have rearrangements of the T cell receptor genes beta, gamma or delta. While some BCP-cell lines express (aberrantly) myeloperoxidase at the mRNA level, most lines are negative in the immunological or cytochemical staining. Several large series documented the difficulty in establishing such BCP cell lines with success rates in the range of 10-20% (on average 15%). Still, since the establishment of the first bonafide BCP-cell line in 1974 (cell line REH), some 150 cell lines have been established of which, however, only a small percentage have been sufficiently well characterized and described. A higher success rate for immortalizing any given leukemia cell might depend on a closer emulation of the physiological in vivo microenvironment. The possibility to grow in vitro leukemia cells at will would represent ideal experimental systems permitting basic research and patient-specific investigations. In summary, the use of well-characterized BCP-cell lines provide unprecedented opportunities for studying a multitude of biological aspects related to normal and neoplastic B-lymphocytes.
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PMID:Establishment and characterization of human B cell precursor-leukemia cell lines. 968 Jan 6

The detection of primitive hematopoietic cells based on repopulation of immune-deficient mice is a powerful tool to characterize the human stem-cell compartment. Here, we identify a newly discovered human repopulating cell, distinct from previously identified repopulating cells, that initiates multilineage hematopoiesis in NOD/SCID mice. We call such cells CD34neg-SCID repopulating cells, or CD34neg-SRC. CD34neg-SRC are restricted to a Lin-CD34-CD38- population without detectable surface markers for multiple lineages and CD38 or those previously associated with stem cells (HLA-DR, Thy-1 and CD34). In contrast to CD34+ subfractions, Lin-CD34-CD38- cells have low clonogenicity in short-and long-term in vitro assays. The number of CD34neg-SRC increased in short-term suspension cultures in conditions that did not maintain SRC derived from CD34+ populations, providing independent biological evidence of their distinctiveness. The identification of this newly discovered cell demonstrates complexity of the organization of the human stem-cell compartment and has important implications for clinical applications involving stem-cell transplantation.
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PMID:A newly discovered class of human hematopoietic cells with SCID-repopulating activity. 973 90

Peptides corresponding to the fusion site in 210 kD BCR-ABL protein b3a2 (p210b3a2) were previously shown to bind to several HLA class I and II alleles. We have found that b3a2 peptide-specific CD4-positive T-helper cells were able to recognize p210b3a2-positive chronic myelogenous leukemia (CML) blasts in a DR4 restricted manner. Until now, there were no reports of b2a2 breakpoint-specific human T-cell responses. Here we show that repetitive stimulation of T lymphocytes with a 17mer peptide covering the fusion region in p210b2a2 also leads to specific T-cell responses. CD4 and CD4/CD8 double-positive clones obtained from a b2a2 peptide-specific cell line were cytotoxic and proliferative in an HLA-DR2a (DRB5*0101) restricted fashion. Autologous Epstein-Barr virus (EBV) transformed cells, expressing BCR-ABL(b2a2) on transfection, and allogeneic HLA-DR matched p210b2a2-positive cells from CML patients were, however, not lysed. BCR-ABL peptide-specific T-cell clones did respond to autologous EBV cells transfected with invariant chain (li) cDNA in which the HLA class II-associated invariant chain peptide (CLIP) was replaced by a BCR-ABL b2a2 fusion oligonucleotide sequence, illustrating the potential of these T cells to recognize an endogenous BCR-ABL(b2a2) ligand.
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PMID:A BCR-ABL oncoprotein p210b2a2 fusion region sequence is recognized by HLA-DR2a restricted cytotoxic T lymphocytes and presented by HLA-DR matched cells transfected with an Ii(b2a2) construct. 1041 96

It was previously shown that patients with chronic myeloid leukemia (CML) have a rare but consistently detectable population of quiescent (G0) leukemic (Philadelphia chromosome-positive and BCR-ABL-positive [BCR-ABL+]) CD34+ cells. In the study described here, most such cells expressed a primitive phenotype (CD38-, CD45RA-, CD71-, and HLA-DR(lo)) and cultures of these cells containing growth factors produced ultimately larger, but initially more slowly growing clones than do cultures of initially cycling CD34+ leukemic cells. Initially quiescent leukemic cells expressing BCR-ABL proliferated in single-cell cultures in the absence of added growth factors, thereby demonstrating their ability to spontaneously exit G0 and enter a continuously cycling state. Interestingly, on isolation, few of these quiescent BCR-ABL+ cells contained either interleukin-3 (IL-3) or granulocyte colony-stimulating factor (G-CSF) transcripts, whereas both were present in most cycling BCR-ABL+ CD34+ cells. However, after 4 days of culture in the absence of added growth factors and in association with their entry into the cell cycle (as indicated by up-regulation of Ki-67 and cdc25 transcripts), IL-3 transcripts became detectable. These findings show that entry of leukemic (BCR-ABL-expressing) progenitors into a quiescent (G0) state in vivo is highest among the most primitive leukemic cell populations, associated with a down-regulation of IL-3 and G-CSF gene expression, and spontaneously reversible in association with up-regulation of IL-3 expression. These results highlight the potential physiologic relevance of quiescent CML progenitors, even in treated patients, in whom these cells would be predicted to have a proliferative advantage over their quiescent normal counterparts when cytokine concentrations are low.
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PMID:Primitive quiescent leukemic cells from patients with chronic myeloid leukemia spontaneously initiate factor-independent growth in vitro in association with up-regulation of expression of interleukin-3. 1115 90

We report a late appearance of the Philadelphia chromosome (Ph) with the p190 BCR/ABL chimeric transcript in a 69-year-old patient with acute myelogenous leukemia (AML) that had evolved from myelodysplastic syndrome (MDS). In July 1997, the patient was found to have pancytopenia caused by refractory anemia with excess of blasts, which evolved into AML in 4 months. The leukemic cells were positive for CD13, CD14, CD33, and HLA-DR and had a normal karyotype. The patient achieved a complete remission after combination chemotherapy. However, his leukemia relapsed in November 1999, with the appearance of leukemic cells positive for CD7, CD13, CD34, and HLA-DR with a 46, XY, add (18) (p11) karyotype. The patient failed to achieve the second remission after several courses of intensive chemotherapy. When the number of blastic cells, showing the same surface phenotypes, in the peripheral blood increased drastically in April 2000, chromosomal analysis of leukemic cells revealed a 46, XY, t(9;22) (q34;q11), add(18)(p11) karyotype. The fusion of the BCR and ABL genes was confirmed by fluorescence in situ hybridization analysis, and the reverse transcription-polymerase chain reaction analysis further revealed the presence of the p190 BCR/ABL chimeric transcript. The appearance of the Ph chromosome in the course of MDS transforming to AML is very rare and may be correlated to the disease progression.
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PMID:[Late appearance of Philadelphia chromosome with the p190 BCR/ABL chimeric transcript in acute myelogenous leukemia progressing from myelodysplastic syndrome]. 1278 57

The role of human leukocyte antigens (HLA) class II molecules in transducing intracellular signals in immune cells is well established. Solid tumors of different histotype can also express HLA class II antigens; however, their intracellular signaling ability is essentially unknown. Due to the frequent expression of HLA class II molecules in primary and metastatic lesions, cutaneous melanoma was utilized to investigate whether the engagement of HLA-DR molecules transduces functional intracellular signal(s). Triggering of HLA-DR molecules by the anti-HLA-DR monoclonal antibody (mAb) L243 induced a significant (P < 0.05) and dose-dependent growth-inhibition of metastatic melanoma cells Mel 120, as well as their homotypic aggregation. Furthermore, an increase in tyrosine phosphorylation of multiple cellular proteins with a molecular weight ranging from 66 to 130 kD, including p125 focal adhesion kinase, was observed. Lastly, the engagement of HLA-DR molecules by mAb L243 inhibited activator protein-1-DNA binding. Thus, HLA-DR molecules expressed on melanoma cells can transduce functional intracellular signals. This finding is consistent with evidences obtained in hematological malignancies, and suggests the potential usefulness of HLA-DR molecules to set-up new approaches of targeted therapy in metastatic melanoma.
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PMID:Targeting of HLA-DR molecules transduces agonistic functional signals in cutaneous melanoma. 1517 97

This study examined the immunomodulatory effect of arvanil, a synthetic capsaicin-anandamide hybrid. Arvanil inhibits lymphocyte proliferation and IFN-gamma production. The phenotype of activated CD4+T cells treated with arvanil shows a down-regulation of T cell activation markers such as CD25, HLA-DR and CD134/OX40. Arvanil and anandamide do not induce apoptosis on CD4+T cells. Arvanil blocks the G1/S phase transition of the cell cycle in stimulated peripheral blood mononuclear cells, inducing activation of p21waf-1/cip-1 and phosphorylation of Akt/PKB. In vivo, arvanil ameliorates experimental autoimmune encephalomyelitis in the SJL/J mouse. Our findings have relevance for the use of arvanil and related compounds as a novel immunotherapeutic approach in the treatment of multiple sclerosis.
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PMID:Arvanil inhibits T lymphocyte activation and ameliorates autoimmune encephalomyelitis. 1623 36


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