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)

The cytogenetic hallmark of chronic myelogenous leukemia (CML) is the Philadelphia chromosome (Ph1), which reflects a chromosomal translocation t(9;22) and a rearrangement of the ABL and bcr genes. This marker is found in all cells arising from the same malignant precursor cell and can be detected in CML cells of the myeloid, monocytic, erythroid, and B-lymphocyte lineage. It is, however, controversial as to whether T lymphocytes of CML patients carry this gene rearrangement. An answer to this question would clarify whether the translocation in CML occurs in a pluripotent hematopoietic stem cell or in a precursor cell already committed to certain lineages, but not the T-cell lineage. To address this question, we established T-cell clones from peripheral venous blood cells of four patients with CML and screened these clones for bcr-abl fusion transcripts by means of polymerase chain reaction and Southern blot analysis. In four T-cell clones of three of these patients, the bcr-abl transcript could be detected. None of 12 T-cell clones of the fourth patient disclosed detectable bcr-abl amplification product. Both CD4+ as well as CD8+ clones displayed fused bcr-abl sequences. These data imply that in CML some but not all T lymphocytes may originate from the Ph1-positive stem cell.
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PMID:Clonal analysis of bcr-abl rearrangement in T lymphocytes from patients with chronic myelogenous leukemia. 137 Oct 78

The expression and function of a receptor tyrosine kinase, c-kit, in the adult bone marrow of the mouse were investigated by using monoclonal antibodies (mAbs) against the extracellular domain of murine c-kit. In adult C57BL/6 mouse, 7.8% of total bone marrow cells express c-kit on their surface. Half of the c-kit+ cells do not express lineage markers including Mac-1, Gr-1, TER-119, and B220, while the remainder coexpress myeloid lineage markers such as Mac-1 and Gr-1. After c-kit+ cells were removed from the bone marrow cell preparation, hemopoietic progenitor cells reactive to IL-3, GM-CSF, or M-CSF and also those which give rise to spleen colonies in irradiated recipients disappeared almost completely. Thus, most hemopoietic progenitors in the adult bone marrow express c-kit. To investigate whether or not c-kit has any role in the hemopoiesis of adult bone marrow, we took the advantage of one of the anti-c-kit mAbs that can antagonize the function of c-kit. As early as two days after the injection of 1 milligram of an antagonistic antibody, ACK2, almost all hemopoietic progenitor cells disappeared from the bone marrow, which eventually resulted in the absence of mature myeloid and erythroid cells in the bone marrow. These results provide direct evidence that c-kit is an essential molecule for constitutive intramarrow hemopoiesis, especially for the self-renewal of hemopoietic progenitor cells at various stages of differentiation.
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PMID:Expression and function of c-kit in hemopoietic progenitor cells. 171 68

Tyrosine phosphorylation is important in the transmission of growth and differentiation signals; known tyrosine kinases include several oncoproteins and growth factor receptors. Interestingly, some differentiated cell types, such as erythrocytes and platelets contain high amounts of phosphotyrosine. We analyzed tyrosine kinases expressed in the K-562 chronic myelogenous leukemia cell line, which has a bipotential erythroid and megakaryoblastoid differentiation capacity. Analysis of 359 polymerase chain reaction-amplified cDNA clones led to the identification of 14 different tyrosine kinase-related sequences (JTK1-14). Two of the clones (JTK2 and JTK4) represent unusual members of the fibroblast growth factor receptor gene family, and the clones JTK5, JTK11, and JTK14 may also belong to the family of receptor tyrosine kinases but lack a close relationship to any known tyrosine kinase. Each of these different genes has its own characteristic expression pattern in K-562 cells and several other human tumor cell lines. In addition, the JTK11 and JTK14 mRNAs are induced during the megakaryoblastoid differentiation of K-562 cells. These tyrosine kinases may have a role in the differentiation of megakaryoblasts or in the physiology of platelets.
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PMID:Putative tyrosine kinases expressed in K-562 human leukemia cells. 224 64

Aluminum (Al) overload in dialysis patients and experimental animals is associated with the development of anemia. However, the precise mechanisms of erythrocyte Al uptake and toxicity are poorly understood. Al accumulation, hemoglobin (Hb) synthesis and cell growth were evaluated in dimethylsulfoxide (DMSO)-induced Friend erythroleukemia cells (FEC), a model system for erythroid differentiation. FEC were grown in media containing either Al citrate, transferrin-aluminum (Tf-Al), Tf or no additions. Al accumulation occurring only in cells grown in Tf-Al containing media was detected at 24 hours and increased linearly up to 96 hours after induction. By 96 hours, 200 +/- 36 micrograms Al/liter lysed cells were detected in Tf-Al grown cells versus 5 +/- 1 micrograms Al/liter lysed cells in cells grown in Al citrate (P less than 0.001). Tf-Al inhibited Hb synthesis at 72 hours after induction. At 96 hours 50 +/- 15% cells were benzidine positive when grown in Tf-Al compared to 76 +/- 15% in Al citrate (P less than 0.001). FEC grown in increasing concentrations of Tf-Al (100 to 500 micrograms/ml) showed inhibition of Hb synthesis at lower concentrations of Tf-Al at 100 micrograms/ml than for cell growth at 300 micrograms/ml. Higher concentrations of Tf-Al (greater than 300 micrograms/ml) did not further inhibit Hb synthesis or cell growth. Iron (Fe) and Tf uptake were increased in Al loaded FEC compared to control cells. The increased Tf uptake was probably the result of increased Tf receptor expression on FES since Tf cell cycling time was unchanged. These data indicate that Al utilizes the Tf uptake pathway for entry into erythrocyte precursors. Al is toxic at sites distal to Fe uptake, possibly at the heme and/or globin synthetic pathways, resulting in decreased Hb synthesis and cell growth.
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PMID:Aluminum inhibits hemoglobin synthesis but enhances iron uptake in Friend erythroleukemia cells. 230 57

We studied the relationship of direct karyotypes, determined at diagnosis and remission, to Abelson-related tyrosine kinase activity and the cytogenetic features of erythroid and myeloid colonies derived from remission marrow of six children with acute lymphoblastic leukemia (ALL). These patients had either the characteristic Philadelphia chromosome (Ph1) [t(9;22)(q34;q11)] or cytogenetically similar variants with a 22q11 breakpoint but no detectable cytogenetic involvement of 9q34. The findings suggested two distinct subtypes of ALL: one defined by t(9;22)(q34;q11) and expression of P185BCR-ABL tyrosine kinase and one with variant karyotypes and no P185BCR-ABL expression. The former comprises cases with Ph1 + marrow cells and Ph1 + erythroid and (or) myeloid colonies in remission marrow and others in which the t(9;22) is undetectable in remission marrow cells. In the latter subgroup, the disease may reflect more extreme mosaicism with a similar stem cell that is cytogenetically undetectable. Variant karyotypes included a del(22)(q11) in one patient and a t(6;22;15;9) (q21;q11;q?22;q21) in another; in both instances, the malignant blast cells lacked P185BCR-ABL expression. Thus ALL with t(9;22)(q34;q11) should be distinguished from ALL with other involvement of the 22q11 breakpoint by molecular studies including protein expression. The diversity of karyotypic findings in cases with involvement of 22q11 suggests at least two mechanisms of leukemogenesis in patients with ALL defined by this breakpoint.
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PMID:Comparative biochemical and cytogenetic studies of childhood acute lymphoblastic leukemia with the Philadelphia chromosome and other 22q 11 variants. 264 73

To examine the in vivo role of c-kit receptor in B lymphopoiesis we have evaluated precursor B cell populations expressing c-kit in mouse bone marrow and the effects on B cell genesis of administering a neutralizing anti-c-kit mAb, ACK2. Double immunofluorescence labeling and mitotic arrest were used to examine bone marrow cells from BALB/c mice. Almost one-half of TdT+ cells and one-quarter of B220+ cells coexpressed c-kit, mainly at low intensities, and were actively proliferating in vivo. c-kit+ cells that lacked B lineage markers expressed c-kit in high intensities and entered mitosis at an exceptionally rapid rate. In ACK2-treated mice, erythroid and granulocytic cells were almost completely absent from the bone marrow, whereas, in contrast, B lymphopoiesis was stimulated. Pre-B cells expressing cytoplasmic mu-chains; as well as TdT+B220+ cells before mu expression, were increased two- to fourfold in number and production rate. IgM-bearing B lymphocytes were increased in bone marrow and spleen. The results demonstrate that many early precursor B cells in mouse bone marrow constitutively express c-kit receptor. The failure of ACK2 treatment to block B lymphopoiesis, however, suggests that c-kit receptor function is not essential for precursor B cell development in vivo, but can be replaced by alternative signaling systems. The stimulation of B cell genesis by ACK2 treatment may reflect a conferred advantage in the competition for microenvironmental factors which underlies the balance between B lymphopoiesis and other hemopoietic lineages in vivo.
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PMID:c-kit expression by B cell precursors in mouse bone marrow. Stimulation of B cell genesis by in vivo treatment with anti-c-kit antibody. 751 30

The mechanisms of the chronic myeloid leukemia (CML) clones proliferative advantage over normal clones are currently unknown. They may involve an insensitivity to a negative regulation of a growth factor-independent proliferation. Clonogenic progenitors from CML patient blood or marrow in chronic phase were grown either in the presence or absence of recombinant growth factors. No erythroid colonies were observed in the absence of any cytokine. In contrast, erythroid colonies composed of fully mature hemoglobinized erythroblasts (day 12 burst-forming units-erythroid) were obtained in the presence of Steel factor (SF) alone. Addition of erythropoietin (Epo) to SF either had no effect on the cloning efficiency or increased up to 50% the number of erythroid colonies. No erythroid growth was observed when cultures were stimulated by interleukin-3 or granulocyte-macrophage colony-stimulating factor alone. Similar erythroid growth in the presence of SF but without Epo was obtained in "serum-free" cultures when purified blood CML CD34+ cells were grown. This growth of erythroid colonies in the absence of Epo was not accounted for by an autocrine stimulation loop by Epo, because neutralizing antibodies against Epo did not inhibit it. This abnormal response to growth factor was specifically observed in the CML clone, as shown by the presence of the BCR-ABL transcript in all of these erythroid colonies. The direct implication of BCR-ABL was further documented (1) by studies of alpha-interferon-treated patients with a chimerism in which the abnormal growth correlates with the presence of the malignant clone and (2) by the use of antisense oligonucleotide against BCR-ABL transcript, which abrogated this abnormal growth. Finally, erythroid growth in the SF presence was greatly diminished by herbimycin A, whereas, at the same concentration, this tyrosine kinase inhibitor had no marked effect on erythroid colony formation in the presence of SF plus Epo on CML or normal marrow cells. This result suggests that the BCR-ABL kinase activity leads directly to this Epo-independent terminal differentiation requiring, however, the presence of SF.
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PMID:Growth of erythroid colonies in chronic myelogenous leukemia is independent of erythropoietin only in the presence of steel factor. 752 39

The protooncogene c-kit encodes a receptor type tyrosine kinase and is allelic with the W locus of mice. SLF, the c-Kit ligand which is encoded by the Sl locus, has growth promoting activity for hemopoietic stem cells. Previous studies demonstrated that c-Kit is functionally required for the proliferation of hemopoietic progenitor cells at various differentiation stages in adult bone marrow. However, the absence of functional SLF and c-Kit in fetuses with mutant alleles of Sl and W loci produces only minor effects on the myeloid and early erythroid progenitor cells in the fetal liver, although the level of the late erythroid progenitor cells is significantly affected. We used an anti-c-Kit monoclonal antibody to investigate the expression and function of c-Kit in murine fetal hemopoietic progenitor cells. Flow-cytometric analysis showed that hemopoiesis in the yolk sac and fetal liver started from cells that express c-Kit. The c-Kit expression decreased upon maturation into erythrocytes in each organ. By fluorescence activated cell sorting, the c-Kit+ cell population was enriched with the hemopoietic progenitor cells clonable in vitro (CFU-E, BFU-E and GM-CFC). To elucidate whether c-Kit functions in these progenitor cells in vivo, we took advantage of the antagonistic anti-c-Kit monoclonal antibody, ACK2, which can block the function of c-Kit. Administration of ACK2 after 12.5 days of gestation rapidly eliminated BFU-E and GM-CFC as well as CFU-E from the fetal liver. However, the number of these progenitor cells in the yolk sac and fetal liver was less affected when the fetuses were given ACK2 before 12.5 days of gestation. Our results provide evidence that there are two waves of hemopoiesis in murine embryos relative to c-Kit dependency. The c-Kit has an essential role on the growth of hemopoietic progenitor cells in the fetal liver after 12.5 days of gestation, whereas the progenitor cells in the liver and yolk sac of the earlier embryo do not depend on c-Kit and its ligand SLF.
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PMID:Expression and function of c-Kit in fetal hemopoietic progenitor cells: transition from the early c-Kit-independent to the late c-Kit-dependent wave of hemopoiesis in the murine embryo. 768 45

Interferon-alpha induces durable cytogenetic remissions in about one-quarter of newly diagnosed patients with chronic myelogenous leukemia (CML). Even so, after short-term follow-up, previous studies have shown that residual leukemic cells can be detected by the polymerase chain reaction (PCR) in all of these individuals. The objectives of our study were therefore to obtain long-term follow-up data on residual disease in a cohort of complete responders and to determine if leukemic cells with clonogenic potential are present in patients despite the absence of relapse. We performed (a) serial analysis of blood and/or bone marrow for a reverse transcriptase PCR amplified BCR-ABL transcript at times well beyond the point that cytogenetic remission was first attained and (b) reverse transcriptase PCR of individually plucked myeloid and erythroid colonies for the presence of the same transcript. Seven CML patients who had previously attained complete cytogenetic remission while on interferon-alpha were investigated. Six of the seven patients were in complete cytogenetic remission at the time of analysis, whereas one patient had early evidence of cytogenetic relapse. With ongoing therapy, five patients with the longest follow-up eventually achieved PCR negativity at time periods of 27, 32, 36, 49, and 67 mo after a complete cytogenetic remission was first noted. Even so, residual disease was detected in progenitor cells derived from two patients, each of whom had been in continuous cytogenetic remission for approximately 2.5 and 3.5 yr, respectively. Progenitors expressing BCR-ABL transcripts were also detected in the patient with early cytogenetic relapse. These observations demonstrate that residual disease resides in colony-forming cells that should have the potential to repopulate the bone marrow. However, the presence of a minority of Ph-positive CML progenitor cells for a very long period of time is still compatible with durable remission, confirming that a situation of tumor dormancy may be induced in CML by interferon therapy.
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PMID:Persistence of dormant leukemic progenitors during interferon-induced remission in chronic myelogenous leukemia. Analysis by polymerase chain reaction of individual colonies. 792 13

The molecular hallmark of Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) is the expression of 1 of 2 alternate forms of the aberrant BCR-ABL protein-p210BCR-ABL or p190BCR-ABL. The presence of BCR-ABL message provides a target for analyzing the lineage derivation of this disease. We, therefore, studied myeloid and erythroid progenitor involvement in Philadelphia chromosome-positive ALL. Bone marrow low-density cells from Philadelphia chromosome-positive ALL patients (5 with the p190BCR-ABL and 2 with the p210BCR-ABL anomaly) were cultured in the mixed colony culture assay. cDNA from individually plucked colony-forming unit-granulocyte-macrophage and burst-forming unit-erythroid colonies was then analyzed using the hybridization protection assay in conjunction with the polymerase chain reaction to detect BCR-ABL molecular aberrations. Colony-forming unit-granulocyte-macrophage and burst-forming unit-erythroid colonies from 1 of 5 p190BCR-ABL-positive patients and 1 of 2 p210BCR-ABL-positive patients expressed BCR-ABL transcripts, whereas colony-forming unit-granulocyte-macrophage and burst-forming unit-erythroid colonies from the other patients did not. Our study suggests that the origin of both p190BCR-ABL- and p210BCR-ABL-positive ALL is heterogenous with involvement of either a pluripotent precursor or a lymphoid lineage-committed hematopoietic progenitor.
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PMID:Heterogeneity in lineage derivation of Philadelphia-positive acute lymphoblastic leukemia expressing p190BCR-ABL or p210BCR-ABL: determination by analysis of individual colonies with the polymerase chain reaction. 832 40


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