Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

FLT3 ligand is a hematopoietic growth factor that plays a key role in growth of primitive hematopoietic cells. FLT3 receptor mRNA is found in early hematopoietic progenitors and in human myeloid leukemia blasts. Much less is known about the surface expression of FLT3 receptor on human hematopoietic cells. Using human 125I-FLT3 ligand, we have identified and characterized surface FLT3 receptors on normal and malignant human hematopoietic cells and cell lines. Our results showed that surface display of FLT3 receptor was greatest in fresh myeloid leukemia blast cells and myeloid leukemia cell lines. Erythroleukemic and megakaryocytic leukemia cell lines (n = 5) bound little to no 125I-FLT3 ligand. Scatchard analysis of 125I-FLT3 ligand binding data shows that three myeloid leukemia cell lines, ML-1, AML-193, and HL-60, as well as normal human marrow mononuclear cells, exhibit high affinity FLT3 receptors. Crosslinking of 125I-FLT3 ligand to FLT3 receptors on the surface of ML-1 myeloid leukemia cells indicates that the FLT3 ligand. The rates of FLT3 ligand internalization and degradation were determined by binding 125I-FLT3 ligand to ML-1 cells and acid stripping to distinguish surface bound from internalized ligand. Internalized 125I-FLT3 ligand was detected within 5 minutes after binding to ML-1 cells. In addition, we evaluated the effect of FLT3 ligand on megakaryocytic colony growth and nuclear endoreduplication, alone or in the presence of thrombopoietin. FLT3 ligand did not promote colony forming unit megakaryocyte (CFU-Meg) colony growth or megakaryocyte nuclear maturation, nor did FLT3 ligand augment the effects of thrombopoietin on these measures of megakaryopoiesis. These data indicate that the FLT3 receptor shares several characteristics with the c-kit receptor including dimerization and rapid internalization. However, the more restricted cellular distribution of the FLT3 receptor may target the effects of FLT3 ligand to primitive hematopoietic cells and to myeloid and lymphoid progenitor cells, in contrast to the pleiotropic effects of the c-kit receptor ligand, stem cell factor.
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PMID:FLT3 receptor expression on the surface of normal and malignant human hematopoietic cells. 889 3

Dendritic cells (DC) are the most efficient APC for T cells. The clinical use of DC as vectors for anti-tumor and infectious disease immunotherapy has been limited by their trace levels and accessibility in normal tissue and terminal state of differentiation. In the present study, daily injection of human Flt3 ligand (Flt3L) into mice results in a dramatic numerical increase in cells co-expressing the characteristic DC markers-class II MHC, CD11c, DEC205, and CD86. In contrast, in mice treated with either GM-CSF, GM-CSF plus IL-4, c-kit ligand (c-kitL), or G-CSF, class II+ CD11c+ cells were not significantly increased. Five distinct DC subpopulations were identified in the spleen of Flt3L-treated mice using CD8 alpha and CD11b expression. These cells exhibited veiled and dendritic processes and were as efficient as rare, mature DC isolated from the spleens of untreated mice at presenting allo-Ag or soluble Ag to T cells, or in priming an Ag-specific T cell response in vivo. Dramatic numerical increases in DC were detected in the bone marrow, gastro-intestinal lymphoid tissue (GALT), liver, lymph nodes, lung, peripheral blood, peritoneal cavity, spleen, and thymus. These results suggest that Flt3L could be used to expand the numbers of functionally mature DC in vivo for use in clinical immunotherapy.
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PMID:Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified. 892 Aug 82

Human bone marrow stromal cell antigen 1 (BST-1) was identified as a glycosylphosphatidyl-inositol-anchored ectoenzyme expressed on bone marrow stromal or synovial cell lines and having the ability to facilitate pre-B cell line growth. The analysis of the expression of mouse BST-1/BP-3 on the surface of lymphoid cells in the bone marrow and thymus revealed that it was very transiently expressed on both B and T cell progenitors undergoing gene rearrangement of the antigen receptor. Among CD45R+ CD43+ B cell progenitors in the bone marrow, BST-1 expression appeared on the CD24 (heat stable antigen)+, CD19+ or CD117 (c-kit)+ population. In the thymus, BST-1 was expressed on CD4-CD8-CD3- [triple negative (TN)] CD90 (Thy-1)+ cells. In TN thymocytes, the majority of CD25+ cells and CD44(10)/- cells expressed BST-1. In fetuses, BST-1+ cells appeared in the thymus and liver at day 14 and 16 of gestation respectively. The expression level of BST-1 by fetal thymus was maximal and > 60% of thymocytes were positive for BST-1 at day 15 or 16 and the proportion then gradually decreased during development. Among day 15 fetal thymocytes, BST-1 was negative on the CD44+ CD25- fraction, very slightly positive on the CD44+ CD25+ fraction, and strongly positive on the CD44(10)/- CD25+ and CD44-CD25- fractions. These results showed that murine BST-1 is a useful marker for lymphoid progenitor cells initiating gene rearrangement of their antigen receptors.
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PMID:Stage-specific expression of mouse BST-1/BP-3 on the early B and T cell progenitors prior to gene rearrangement of antigen receptor. 892 17

Morphologic, immunologic, cytogenetic, and clinical features were studied in 9 cases of acute undifferentiated leukemia (AUL). These patients were unclassifiable by FAB criteria, they were CD34+ and did not express myeloid- or lymphoid-associated antigens (CD13, CD33, CD14, CD15, CD61, CD19, CD10, CD22, CD7, CD2, CD5, CD3). Clonal abnormalities were seen in 8 of 9 cases. Del(5q) as the sole anomaly was observed in 3 cases; +13 was the primary change in 3 cases, and isolated trisomy 12 was found in 1 patient. A complex karyotype with trisomy 12q, in association with del 17p and trisomy 21q was detected in 1 case. One patient with 5q- relapsed with refractory anemia with excess of blasts; the presence of dysgranulopoiesis and a few blasts with possible monocytoid morphology in the remaining 2 patients point to a "myeloid nature" of these leukemias. Analysis of cytologic features in our 3 patients with +13, in combination with previously reported cases, suggests the occurrence of immature stem cell involvement with limited differentiation potential, possibly more along the myeloid than the lymphoid lineage. The significance of trisomy 12q in this subset of leukemia remains elusive; some clues of minimal differentiation towards the myeloid lineage in our cases are provided by positivity for the CD117 (c-kit) antigen and by relapse with acute myeloid leukemia without maturation (M1) in one patient. We conclude that, with presently available diagnostic techniques, AUL is a rare subset of leukemia, in which cytogenetic changes are confined to a few chromosomes, with prevalent involvement of 5q and of chromosomes 13 and 12. Chromosome findings may be of value in clinical practice, especially in those cases with "myeloid-oriented" karyotype.
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PMID:Cytogenetic and clinicobiological features of acute leukemia with stem cell phenotype: study of nine cases. 895 68

The receptor-type tyrosine kinase, c-kit is expressed in hematopoietic stem cells (HSC), myeloid, and lymphoid precursors. In c-kit ligand-deficient mice, absolute numbers of HSC are mildly reduced suggesting that c-kit is not essential for HSC development. However, c-kit- HSC cannot form spleen colonies or reconstitute hematopoietic functions in lethally irradiated recipient mice. Based on in in vitro experiments, a critical role of c-kit in B-cell development was suggested. Here we have investigated the B-cell development of c-kit-null mutant (W/W) mice in vivo. Furthermore, day 13 fetal liver cells from wild type or W/W mice were transferred into immunodeficient RAG-2-/- mice. Surprisingly, transferred c-kit- cells gave rise to all stages of immature B cells in the bone marrow and subsequently to mature conventional B2, as well as B1, type B cells in the recipients to the same extent as transferred wild type cells. Hence, in contrast to important roles of c-kit in the expansion of HSC and the generation of erythroid and myeloid lineages and T-cell precursors, c-kit- HSC can colonize the recipient bone marrow and differentiate into B cells in the absence of c-kit.
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PMID:Interactions between c-kit and stem cell factor are not required for B-cell development in vivo. 900 54

Signaling through c-Kit/stem cell factor (SCF) is crucial for normal development of erythroid and myeloid hematopoietic precursors and of melanocytes and germ cells. While peripheral lymphoid populations of W/Wv and SI/SId mice appear normal, we demonstrated that the intraepithelial lymphocyte (IEL) populations of small (SI) and large (LI) intestine were significantly affected. IEL populations of young W/Wv animals were indistinguishable from those of their control littermates, but an age-dependent decrease in SI and LI TCRgamma delta IEL occurred in c-Kit mutant mice. In SI, but not in LI, this diminution was accompanied by gross expansion of TCRalpha beta IEL that resulted in significantly increased IEL:epithelial cell ratios in c-Kit mutant mice. Bromodeoxyuridine labeling studies revealed that the increase in cell numbers was due to lymphoproliferation that occurred in situ. Interestingly, TCRgamma delta IEL expressed cell surface c-Kit, while the expanding population of TCRalpha beta IEL did not. Analysis of radiation bone marrow chimeras demonstrated that the dysregulation required either disruption of stromal cell SCF or IEL c-Kit and showed that the effect on IEL or their precursors was not due to other changes in the intestinal microenvironment. Lamina propria T cell populations in these mice were unaffected, reinforcing the idea that the developmental requirements of these gut-resident lymphocyte populations are distinct. Overall, the results demonstrated that the development of intestinal TCRgamma delta IEL, regardless of location, shares common requirements for SCF, while SI and LI TCRalpha beta IEL may develop along distinct pathways. Possible mechanisms for the loss of proliferative regulation in gut T cells in c-Kit/SCF deficiency are discussed.
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PMID:Age-dependent intestinal lymphoproliferative disorder due to stem cell factor receptor deficiency: parameters in small and large intestine. 901 87

Relatively little is known about the relationship of lymphoid-associated gene expression to the proliferation and differentiation potential of early human bone marrow lymphoid progenitors. Surface expression of interleukin-7 (IL-7) receptor-alpha (IL-7R alpha), a component of the high-affinity receptor for the lymphoid precursor growth factor IL-7, defined a CD34+ progenitor subset lacking the CD19+ pro-B phenotype but demonstrating markedly enhanced lymphoid clonogenic capacity and the ability to differentiate into pro-B cells in short-term culture. These progenitors expressed mRNA for the lymphoid-associated genes Ig beta, RAG-1, and PAX-5, and were uniformly TdT-positive (TdT+). In contrast, IL-7R alpha-/CD19-/ CD34+ progenitors had a 50-fold reduced lymphoid clonogenic capacity and did not differentiate into pro-B cells in short-term culture. Expression of TdT and the lymphoid-associated genes Ig beta and RAG-1, but not PAX-5, was detected in this fraction, although at lower levels than in the IL-7R alpha+ progenitors. In contrast to IL-7R alpha, loss of the stem cell factor receptor c-kit was associated with enhanced lymphoid clonogenic potential and increased B-lineage differentiation potential. These results indicate that IL-7R alpha expression defines entry into a developmental stage characterized by upregulation of multiple lymphoid-associated genes and enhanced fitness for B-lymphoid differentiation. The onset of IL-7R alpha and PAX-5 expression immediately before acquisition of CD19 is consistent with evidence suggesting upregulation of CD19 through pathways involving PAX-5 and IL-7.
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PMID:Expression of interleukin-7 receptor by lineage-negative human bone marrow progenitors with enhanced lymphoid proliferative potential and B-lineage differentiation capacity. 902 24

The Pax5 gene coding for the transcription factor BSAP has an essential role in B lymphopoiesis and midbrain development. Here we present a detailed analysis of the B-cell phenotype of Pax5 mutant mice that revealed a differential dependency of fetal and adult B lymphopoiesis on this transcriptional regulator. B-cell development is arrested in the bone marrow at the early pro-B (pre-BI) cell stage, which is characterized by expression of the early markers c-kit, CD43, lambda5, VpreB, and HSA and the absence of the later markers CD25 and BP-1. These pre-BI cells fail to express the BSAP target gene CD19 and are capable of long-term proliferation in vitro in the presence of stromal cells and IL-7. B-lymphoid progenitors could not be detected in the fetal liver of Pax5 mutant embryos. However, Pax5-deficient fetal liver cells gave rise to the development of pre-BI cells in bone marrow on transplantation into lethally irradiated mice. These data indicate different functions of Pax5 in the distinctive microenvironments of fetal liver and adult bone marrow. As shown by PCR analyses, the pre-BI cells in Pax5-deficient bone marrow have undergone D(H)-to-J(H) rearrangement of the immunoglobulin heavy-chain locus at normal frequency. In contrast, V(H)-to-D(H)J(H) rearrangements were reduced approximately 50-fold in Pax5-deficient pre-BI cells, suggesting a role for Pax5 in the developmental pathway controlling V-to-DJ recombination.
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PMID:Essential functions of Pax5 (BSAP) in pro-B cell development: difference between fetal and adult B lymphopoiesis and reduced V-to-DJ recombination at the IgH locus. 904 61

Hemopoiesis, initiated in the early embryo yolk sac (YS) (7.5-8 days postcoitum (pc) in mouse), takes place thereafter in sites successively seeded by extrinsic hemopoietic stem cells (HSC). Since the existence of intraembryonic HSC has been proven experimentally in some vertebrates, it is also likely that not all HSC originate in the YS in mammals, as previously thought. Candidate intraembryonic sites that may be active in producing HSC before liver colonization are the para-aortic splanchnopleura (P-Sp) and the aorta-gonads-mesonephros region (AGM). Here we explore these sites directly for the presence of cells with hemopoietic-specific surface molecules and gene activities. The Ags c-kit, AA4.1, Mac-1, and Sca-1 begin to be expressed on some P-Sp and AGM cells, making it possible to distinguish subpopulations that evolve according to reproducible developmental patterns. On the basis of RAG-1 gene transcription, the first lymphoid precursors in the mouse embryo appear to be present 9.5 to 10 days pc in P-Sp/AGM and YS. Starting B-cell lymphopoiesis (9-12 days pc) is characterized by nonexpression of the surrogate light chain lambda 5-encoding gene and biased usage of IgH DJ4 rearrangements. In the 12.5- to 13.5-day-pc fetal liver (FL), a switch occurs, characterized by the random use of all IgH DJ and the detection of lambda 5 gene transcripts.
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PMID:Antigenic phenotype and gene expression pattern of lymphohemopoietic progenitors during early mouse ontogeny. 905 95

In the hematopoietic lineage, the transcription factors GATA-1 and GATA-2 show restricted and largely overlapping expression profiles, but GATA-2 is uniquely expressed in early hematopoietic progenitors. GATA-3 is found exclusively in T cells of hematopoietic lineage. To clarify whether these expression profiles are preserved or changed during the development of malignancies, we analyzed the expression of GATA factors in the blasts from leukemic children. A total of 18 myelogenous leukemia and 24 lymphoblastic leukemia (ALL) cases were investigated. In the majority of the former cases, GATA-2 mRNA expression and the expression of CD34 and c-kit antigens on leukemic cells were demonstrated. In contrast, GATA-2 mRNA and c-kit antigen could not be detected in CD34-positive cells from ALL patients. GATA-3 mRNA was expressed in all T-ALL cases, but not in any precursor B-ALL. These findings suggest that down-regulation of GATA-2 and expression of GATA-3 are important events for the commitment of cells to lymphoid and T cell lineage, respectively. The expression profiles of GATA factors in leukemic cells are generally consistent with those in their normal counterparts, and thus provide a useful tool to determine the lineage commitment of unclassified leukemia.
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PMID:Expression of GATA transcription factors in myelogenous and lymphoblastic leukemia cells. 911 95


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