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)

The presence of Philadelphia chromosome t(9:22) is a hallmark of 95% of clinical cases of chronic myelogenous leukemia (CML) as well as 20% of adult acute lymphoblastic leukemia (ALL) and 5% of acute myeloid leukemia (AML). The product of t(9;22) is a fusion protein BCR-ABL. The fusion proteins of CML, ALL and AML have increased tyrosine kinase activity and show a transforming potential in vitro and in animal models. The shorter p190 protein is associated almost only with ALL and AML, while the protein p210 is present in both chronic phase and blast crisis of CML and also in 50% of Philadelphia-positive (Ph1+) ALL. In CML the transition from chronic phase to blast crisis is usually accompanied by additional genetic events, e.g. additional chromosomal abnormalities, and oncogene activation(s). The detailed understanding of molecular basis of CML, and Ph1+ ALL and AML provides highly sensitive molecular and serological methods to complement classical cytogenetics. The advantages and limitations of these techniques are described and discussed below.
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PMID:Molecular pathology of chronic myelogenous leukemia. 224 53

Double fluorescence in situ hybridization was used to detect Philadelphia (Ph) chromosomes in interphase nuclei and metaphases of patients with chronic myeloid leukemia. Application of cosmid probes for 3' ABL and 5' BCR sequences gave better results than libraries for chromosomes 9 and 22. The present approach may provide an alternative method for monitoring minimal residual disease in Ph+ CML patients.
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PMID:Detection of the Philadelphia chromosome in interphase nuclei. 226 53

Chronic myelogenous leukemia (CML) is characterized by the presence of a novel fusion gene comprised of portions of the BCR gene from chromosome (ch) 22 and the ABL gene from ch 9. The present study was designed to identify regulatory DNA regions as determined by DNAase I hypersensitivity to address the question of whether altered chromatin contributes to changes in ABL expression. We identify five hypersensitive (HS) sites within the abnormal BCR/ABL allele in K562 cells in a pattern different from the normal BCR. The pattern of hypersensitivity is modified when the cells undergo hemin induced differentiation. These results indicate that the normal BCR has a chromatin configuration consistent with active transcription and that the BCR/ABL fusion gene chromatin is different. This may be important in the pathogenesis of CML.
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PMID:Chromatin alterations surrounding the BCR/ABL fusion gene in K562 cells. 226 34

A patient with Philadelphia (Ph1)-negative, breakpoint cluster region (bcr)-positive chronic myeloid leukemia (CML) is reported. Pulsed-field gel electrophoretic analysis demonstrated the comigration of both ABL and BCR sequences on the same BssHII and SacII fragment. Moreover, in situ hybridization studies demonstrated that ABL sequences had been moved from band 9q34 to 22q11 and that the additional t(12;12)(q13;p12) was not involved in the ABUBCR related translocation. Nevertheless, a possible role of oncogenes or regulatory sequences activated or inhibited by the additional translocation cannot be excluded.
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PMID:Molecular and cytogenetic studies of a patient with Philadelphia-negative, BCR-positive chronic myeloid leukemia and t(12;12)(q13;p12). 227 60

We report on eight patients who were 35 to 77 years old with an isochromosome 17q as the sole structural chromosomal anomaly. Additional numerical chromosomal changes were a trisomy 8 or 17 in two cases each and a trisomy 19 in one case. Five patients had myelodysplastic syndrome (MDS) diagnosed according to the FAB nomenclature as chronic myelomonocytic leukemia (CMML) in two cases, refractory anemia with excess of blasts in transformation (RAEBt) in two cases, and refractory anemia with excess of blasts (RAEB) in one case. One patient suffered from a myeloproliferative disorder (MPS). All cases progressed to acute nonlymphocytic leukemia (ANLL) type M1, M2, or M4 in a period of 2 to 30 months after initial diagnosis, except one patient with RAEBt who died within 2 months. Two patients presented with ANLL-M2 at time of diagnosis. Treatment during the chronic phase of disease consisted of mild cytoreduction and/or substitution of platelets or red blood cells. One patient with CMML received an allogeneic bone marrow graft and relapsed after 33 months with ANLL-M1. Treatment results for overt leukemia were poor, and survival was short, lasting from 1 to 4 months. Overall survival was 1 to 37 months (median duration, 6.5 months). Molecular studies in two cases revealed neither a BCR rearrangement nor a translocation of the ABL protooncogene, as observed in Ph1-positive chronic myeloid leukemia (CML). Thus, an i(17q) anomaly seems to identify a distinct subgroup of mostly myelodysplastic and, less frequently, myeloproliferative disorders that progress rapidly to ANLL, respond poorly to chemotherapy, and are associated with short survival after transformation.
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PMID:Isochromosome 17q in Ph1-negative leukemia: a clinical, cytogenetic, and molecular study. 222 38

A number of protooncogenes have been implicated in human tumorigenesis. The ABL oncogene is consistently rearranged and activated as a consequence of the translocation t(9;22) that gives rise to the Philadelphia chromosome in chronic myeloid leukemia and in some cases of acute lymphoblastic leukemia. Here we describe rearrangement of ABL in a different type of malignancy. The glioblastoma cell line A172 lacks germline alleles of ABL. A recombination event, presumably followed by a duplication, has created two ABL alleles in which exon 11 is joined to chromosome 16 sequences. Although the main body of ABL exons was still present, two considerably shortened ABL mRNAs of 3.8 and 2.8 kilobases were detected; the 3.8-kilobase mRNA hybridized exclusively to an exon IB probe. Neither mRNA hybridized to an ABL probe encompassing part of the tyrosine kinase domain. Thus, the cell line A172 is able to survive in the absence of a functional ABL gene product, indicating that the role of ABL is unlikely to be "housekeeping."
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PMID:Rearrangement of the human ABL oncogene in a glioblastoma. 233 39

A patient who was diagnosed with chronic myeloid leukemia remained in chronic phase for 14 years before progressing into a lymphoid blast crisis in 1983. The acute phase was successfully treated, and the patient has remained in an indolent chronic phase to date. Cytogenetic and molecular analysis during this second chronic phase confirm the presence of the Philadelphia chromosome and its transcribed BCR-ABL mRNA. The breakpoint within M-bcr occurred in the 3' portion of the region and expressed a hybrid joining the b3 exon of BCR to the a2 exon of ABL.
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PMID:Molecular analysis of a CML patient with a long duration of chronic phase before and after lymphoid blast crisis. 235 47

Relapse of chronic myelogenous leukemia after bone marrow transplantation can be detected by using clinical, cytogenetic, or molecular tools. A modification of the polymerase chain reaction can be used in patients to detect low levels of the BCR-ABL-encoded mRNA transcript, a specific marker for chronic myelogenous leukemia. Early detection of relapse after bone marrow transplantation could potentially alter treatment decisions. We prospectively evaluated 19 patients for evidence of molecular relapse, cytogenetic relapse, and clinical relapse after bone marrow transplantation. We used the polymerase chain reaction to detect residual BCR-ABL mRNA in patients followed up to 45 months after treatment (median, 15 months; range, 6-45 months) and found 4 patients with BCR-ABL mRNA expression following bone marrow transplantation. In 2 patients BCR-ABL mRNA was detected in all samples, and both have developed cytogenetic relapse. In 1 patient BCR-ABL mRNA was detected transiently during the first month after transplant but was undetectable thereafter. The fourth patient had BCR-ABL mRNA 6 months after bone marrow transplantation but not in prior samples. Fifteen patients did not express detectable BCR-ABL mRNA. All 19 patients remain in clinical remission. In this prospective study of chronic myelogenous leukemia patients treated with bone marrow transplantation, molecular relapse preceded cytogenetic relapse in those patients who persistently express BCR-ABL mRNA. We recommend using standard clinical and cytogenetic testing to make patient care decisions until further follow-up determines the clinical outcome of those patients with residual BCR-ABL mRNA transcripts detected by polymerase chain reaction.
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PMID:Molecular relapse in chronic myelogenous leukemia patients after bone marrow transplantation detected by polymerase chain reaction. 240 84

Cellular or proto-oncogenes are normal cellular genes important in normal cell growth and development. In some instances abnormal expression of these genes is associated with altered cell growth or with malignant transformation. Abnormalities of cellular oncogenes are common in human leukemias. These arise by multiple mechanisms such as mutation, translocation, amplification, and others. Sometimes more than one abnormality is present within a single oncogene. In other instances, a leukemia cell may contain abnormalities of several different oncogenes. Some oncogene abnormalities are relatively specific for certain leukemias and occur in almost all cases; examples include ABL in chronic myelogenous leukemia or MYC in Burkitt leukemia/lymphoma. Other abnormalities are also relatively specific but occur in only some cases such as NRAS in acute myelogenous leukemia or BCL2 in B-cell acute lymphoblastic leukemia. In other leukemias, such as most cases of acute lymphoblastic leukemia and chronic lymphocytic leukemia, oncogene abnormalities are uncommon. The precise role of oncogenes in the pathogenesis of human leukemia is unknown. Retrovirus transduced versions of some of the oncogenes modified in human leukemias cause leukemia in animals. Other oncogenes, modified or unmodified, transform animal and human hematopoietic cells in vitro. Some oncogene products are hematopoietic growth factors or growth factor receptors while others regulate cell proliferation or differentiation by diverse mechanisms. Disruption of the balance between these processes seems the most likely mechanism of oncogene related leukemogenesis. If the role of oncogenes in human leukemias can be defined, innovative diagnostic and therapeutic strategies may be forthcoming.
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PMID:Oncogenes and leukemia. 240 17

An aberrant p210BCR-ABL protein that possesses constitutive protein-tyrosine kinase activity is presumed to be involved in the development of the neoplastic phenotype in chronic myelogenous leukemia (CML). Using a highly specific antibody against phosphotyrosine, we have isolated the tyrosine-phosphorylated p210BCR-ABL and several other proteins containing phosphotyrosine from a variety of CML cell lines. p210BCR-ABL isolated by the monoclonal anti-phosphotyrosine antibody possessed protein-tyrosine kinase activity in vitro comparable to that of the p210BCR-ABL isolated by antibody to a specific peptide sequence in the ABL protein-tyrosine kinase. Other prominent proteins containing phosphorylated tyrosine residues were observed at 185, 150, 120, 105, 63, 56, 36, and 32 kDa, and less prominent proteins were observed at 195, 155, 94, 53, 40, and less than 29 kDa. Staphylococcal V8 peptide mapping indicated that proteins of similar molecular weights were highly homologous to each other across cell lines, despite the diverse hematopoietic lineages of these cells and the genetic heterogeneity of the patients from whom the CML cell lines were derived. Phosphopeptide mapping also revealed that these proteins were distinct from each other as well as from p210BCR-ABL. Because virtually identical phosphotyrosine-containing proteins were found in peripheral blood leukocytes taken directly from CML patients, these proteins are not an artifact of long-term tissue culture but appear to be an integral part of the CML phenotype.
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PMID:Cell lines and peripheral blood leukocytes derived from individuals with chronic myelogenous leukemia display virtually identical proteins phosphorylated on tyrosine residues. 244 21


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