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)

Analysis of the cellular/molecular basis of the early steps of hematopoietic proliferation and differentiation is hindered by the rarity of hematopoietic progenitors and stem cells (HP/HSC). The intensive efforts devoted to the development of purification methods for early HP and HSC, although initially largely unsuccessful, have recently provided a high level of HP/HSC yield and/or recovery. The methodology developed by our group, recently improved, provides not only virtually complete purification, but also abundant recovery of early HP/HSC such as colony forming units granulocyte/erythroid/macrophage/megakaryocyte (CFU-GEMM), burst forming units erythroid (BFU-E), CFU granulocyte/macrophage (CFU-GM)/CFU blast cells (CFU-B), and long-term culture initiating cells (LTC-IC) from adult peripheral and cord blood (CB). We have also developed a serum-free liquid suspension culture for unilineage erythroid (E), granulocytic (G) or monocytic (M) differentiation of stringently purified HP/HSC. These culture systems allow sequential collection and cellular/molecular analysis of discrete populations of hematopoietic cells at a homogenous stage of differentiation specifically along a unilineage pathway. These experimental tools have been utilized to investigate cellular/molecular mechanisms underlying early hematopoiesis. The transcription factor (TF) GATA-1 is considered to be the "master" gene of erythropoiesis. In highly purified HP/HSC undergoing E or GM differentiation, GATA-1 expression is characterized initially by proliferation-dependent activation and at later stages by sustained expression in the E pathway and suppression in the GM pathway. Hypothetically, similar on/off switches of lineage-restricted TF may underlie the binary fate decisions of early HP differentiation. The expression and modulation of hematopoietic growth factor receptors (HGFR) in early hematopoiesis have been extensively analyzed. The results suggest a model of transactivation cascade for HGFR such as interleukin 6 receptor (IL-6R), IL-3R, GM colony stimulating factor receptor (GM-CSFR), and erythropoietin receptor (EpR), whereby each HGF upmodulates the R(s) for distal-acting HGF(s). Finally, we have investigated the effect of HGF on reactivation of hemoglobin F (HbF) in clonogenic or liquid suspension serum-free culture of purified adult HP. The results suggest that c-kit ligand (KL) plays a key role in the reactivation of HbF synthesis in adult life, and IL-3/GM-CSF potentiate this effect at low KL level. The KL-induced HbF reactivation is seemingly related to an enhanced proliferation of early E progenitors in their differentiation pathway.
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PMID:Stringently purified human hematopoietic progenitors/stem cells: analysis of cellular/molecular mechanisms underlying early hematopoiesis. 824 48

Cytokines play a crucial role in the differentiation and proliferation of hemopoietic cells, and it has recently been found that adhesion molecules play crucial roles not only in differentiation and proliferation, but also in the homing and other functions of hemopoietic cells. We have very recently established a new method for purifying pluripotent hemopoietic stem cells (P-HSC) in mice by injecting 5-fluorouracil (5-FU). The P-HSC were found to be low-density, lineage marker-negative (Lin-), CD71- and major histocompatibility complex class I(high). In the present study, we analyze changes in the expression of various HSC markers (Sca-1 and CD34), receptors (c-kit and interleukin-6 receptor [IL-6R]) and adhesion molecules (very late activation antigen-4 [VLA-4], lymphocyte function-associated antigen-1 [LFA-1], and CD44) after 5-FU injection. The percentage of Sca-1+ cells increases after 5-FU treatment, reaching a maximum on day 3, whereas the percentage of IL-6R+ cells decreases, reaching a minimum on day 3. The percentage of CD34+ cells does not change after 5-FU treatment. The percentages of both c-kit(low) and c-kit(high) cells decrease, reaching a minimum on day 3 after 5-FU treatment, whereas the percentage of c-kit- cells reciprocally increases, reaching a maximum on day 3. However, there is no change in the expression of adhesion molecules (VLA-4, LFA-1 and CD44) on the P-HSC.
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PMID:Changes in markers, receptors and adhesion molecules expressed on murine hemopoietic stem cells after a single injection of 5-fluorouracil. 888 99

The engraftment potential of murine stem cells (HSC) is greatly reduced when these cells are expanded in vitro with stem cell factor and interleukin-3. We have evaluated if the addition of MIP-1 alpha or LIF to these cultures would protect the ability of murine wild type HSC to engraft the stem cell defective W/Wv recipient. In this transplantation model red and white blood cell reconstitution is assessed by hemoglobin electrophoresis and c-kit PCR genotyping, respectively. The results obtained indicate that both MIP-1 alpha and LIF protect, at least transiently, the HSC repopulating ability in vivo in spite of the modest expansion in the number of nucleated and progenitor cells observed.
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PMID:Macrophage inflammatory protein-1 alpha (MIP-1 alpha) and leukemia inhibitory factor (LIF) protect the repopulating ability of purified murine hematopoietic stem cells in serum-deprived cultures stimulated with SCF and IL-3. 1072 Dec 26

Functional recovery of the immune system is critical for long-term survival in hematopoietic stem cell transplant recipients. In this study, two donor-recipient allogeneic transplant settings (haploidentical and fully mismatched) are used to investigate the functional activity of donor-derived B and T cells in animals grafted with purified c-kit(+), Thy 1.1(lo), Lin(-/lo), and Sca-1(+) hematopoietic stem cells (KTLS HSC).Ovalbumin-specific immunoglobulin G, polyclonal immunoglobulin isotypes, and B- and T-cell proliferation were examined on the recipients who received haploidentical or fully mismatched HSC.A severe deficiency of antigen-specific immunoglobulin response occurs in fully engrafted mice that received KTLS HSC from fully mismatched, but not haploidentical, donors. This lack of B-cell-specific immunity is not due to a deficiency of polyclonal immunoglobulins in serum. B cells from both fully mismatched and haploidentical recipients proliferate normally after stimulation with anti-mu and the percentage of mature B cells is normal. The T-cell response to anti-CD3 in fully mismatched recipients was much weaker than that of their untransplanted controls. However, T cells from haploidentical recipients respond normally to anti-CD3. This study demonstrates that numerical recovery of donor-derived cells in the periphery of recipients does not represent a functional reconstitution, particularly in animals that receive fully mismatched transplants. Defects of specific B-cell immunity and T-cell proliferation are observed in fully mismatched, purified HSC transplant recipients with a quantitative recovery within the normal range of donor-derived lymphocytes.
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PMID:Differing functional recovery of donor-derived immune cells after purified haploidentical and fully mismatched hematopoietic stem cell transplantation in mice. 1114 70

Several homeobox transcription factors, such as HOXB3 and HOXB4, have been implicated in regulation of hematopoiesis. In support of this, studies show that overexpression of HOXB4 strongly enhances hematopoietic stem cell regeneration. Here we find that mice deficient in both Hoxb3 and Hoxb4 have defects in endogenous hematopoiesis with reduced cellularity in hematopoietic organs and diminished number of hematopoietic progenitors without perturbing lineage commitment. Analysis of embryonic day 14.5 fetal livers revealed a significant reduction in the hematopoietic stem cell pool, suggesting that the reduction in cellularity observed postnatally is due to insufficient expansion during fetal development. Primitive Lin(-) ScaI(+) c-kit(+) hematopoietic progenitors lacking Hoxb3 and Hoxb4 displayed impaired proliferative capacity in vitro. Similarly, in vivo repopulating studies of Hoxb3/Hoxb4-deficient hematopoietic cells resulted in lower repopulating capability compared to normal littermates. Since no defects in homing were observed, these results suggest a slower regeneration of mutant HSC. Furthermore, treatment with cytostatic drugs demonstrated slower cell cycle kinetics of hematopoietic stem cells deficient in Hoxb3 and Hoxb4, resulting in increased tolerance to antimitotic drugs. Collectively, these data suggest a direct physiological role of Hoxb4 and Hoxb3 in regulating stem cell regeneration and that these genes are required for maximal proliferative response.
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PMID:Reduced proliferative capacity of hematopoietic stem cells deficient in Hoxb3 and Hoxb4. 1274 89

Endoglin, an ancillary TGF-beta receptor, is differentially expressed in long-term repopulating hematopoietic stem cells (LTR-HSC). Here, we describe simple and highly efficient purification schemes for mouse bone marrow LTR-HSCs using Endoglin as a marker. The Endoglin positive and Sca-1 positive (Endo(Pos) Sca-1(Pos)) population, which contains about 36% of "Side Population" (SP) cells, is highly enriched for LTR-HSCs. In long-term competitive reconstitution assays, 100 such cells reconstituted all lethally irradiated recipients. Interestingly, the Endo(Pos) Sca-1(Pos) population contains comparable LTR-HSC activity in both SP and non-SP fractions, indicating that many HSCs are not captured by the SP phenotype. Furthermore, LTR-HSCs are exclusively found in the Endo(Pos) Sca-1(Pos) Lin(Neg/Low) (lineage negative/low), but not in the Endo(Neg) Sca-1(Pos) Lin(Neg/Low) population, suggesting that the Endo(Pos) population may contain all LTR-HSCs in mouse bone marrow. Finally, we demonstrated that the Endo(Pos) Sca-1(Pos) Rh(Low) (Rhodamine-123 low) phenotype, without using CD34, c-Kit, or Lineage markers, defines a nearly homogenous population of LTR-HSCs.
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PMID:The endoglin(positive) sca-1(positive) rhodamine(low) phenotype defines a near-homogeneous population of long-term repopulating hematopoietic stem cells. 1456 17

Several reports have shown that the expression of Sca-1 (Ly-6A/E), the most widely used murine hematopoietic stem cell marker, is restricted to blood vessels in several nonhematopoietic tissues. However, there is no information about which components are expressing Sca-1, and what the role of Sca-1 could be. Because we have previously shown that murine liver endothelial cells from the hepatic sinusoid (LSEC) express some HSC markers (i. e., CD34 and c-kit), we hypothesized that these cells could also express Sca-1. In this work, we show that Sca-1 is constitutively expressed in LSEC, as well as in the liver sinusoid lumen. The expression of Sca-1 in LSEC was confirmed at the mRNA and protein level by reverse transcriptase (RT)-PCR, flow cytometry, and immunofluorescence studies. The expression of Sca-1 was enhanced on the surface of LSEC by tumor necrosis factor (TNF). We examined whether Sca-1 ligation on the surface of LSEC regulates some biological response in these cells. Our results show that ligation of Sca-1 by the anti-Ly-6A/E monoclonal antibody (mAb) D7 stimulated the growth of LSEC and the production of interleukin-6 (IL-6) by these cells. To our knowledge, this is the first report that LSEC express Sca-1, which may constitute additional support to the theory of a common progenitor for the hematopoietic and endothelial cells. Our results show a novel role of Sca-1, indicating that it induces activation of LSEC to proliferate and to produce IL-6. These results suggest that Sca-1 may participate in several clinical conditions such as angiogenesis and inflammation.
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PMID:Expression of the hematopoietic stem cell antigen Sca-1 (LY-6A/E) in liver sinusoidal endothelial cells: possible function of Sca-1 in endothelial cells. 1558 10

The hematopoietic system develops during embryogenesis at temporally and anatomically restricted sites. The anatomical origin of definitive HSCs is not fully resolved, and little is known about how the different fetal hematopoietic microenvironments direct HSC development. Here, we show that the mouse placenta functions as a hematopoietic organ that harbors a large pool of pluripotent HSCs during midgestation. The onset of HSC activity in the placenta parallels that of the AGM (aorta-gonad-mesonephros) region starting at E10.5-E11.0. However, the placental HSC pool expands until E12.5-E13.5 and contains >15-fold more HSCs than the AGM. The expansion of the CD34(+)c-kit(+) HSC pool in the placenta occurs prior to and during the initial expansion of HSCs in the fetal liver. Importantly, the placental HSC pool is not explained by rare circulating HSCs, which appear later. These data support an important, but unappreciated, role for the placenta in establishing the mammalian definitive hematopoietic system.
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PMID:The placenta is a niche for hematopoietic stem cells. 1573 22

Imatinib mesylate (IM) is a tyrosine kinase inhibitor, which inhibits phosphorylation of downstream proteins involved in BCR-ABL signal transduction. It has proved beneficial in treating patients with chronic myeloid leukaemia (CML). In addition, IM demonstrates activity against malignant cells expressing c-kit and platelet-derived growth factor receptor (PDGF-R). The activity of IM in the blastic crisis of CML and against various myeloma cell lines suggests that this drug may also target other cellular components. In the light of the important role of telomerase in malignant transformation, we evaluated the effect of IM on telomerase activity (TA) and regulation in various malignant cell lines. Imatinib mesylate caused a dose-dependent inhibition of TA (up to 90% at a concentration of 15 microM IM) in c-kit-expressing SK-N-MC (Ewing sarcoma), SK-MEL-28 (melanoma), RPMI 8226 (myeloma), MCF-7 (breast cancer) and HSC 536/N (Fanconi anaemia) cells as well as in ba/F3 (murine pro-B cells), which do not express c-kit, BCR-ABL or PDGF-R. Imatinib mesylate did not affect the activity of other DNA polymerases. Inhibition of TA was associated with 50% inhibition of proliferation. The inhibition of proliferation was associated with a decrease in the S-phase of the cell cycle and an accumulation of cells in the G2/M phase. No apoptosis was observed. Inhibition of TA was caused mainly by post-translational modifications: dephosphorylation of AKT and, to a smaller extent, by early downregulation of hTERT (the catalytic subunit of the enzyme) transcription. Other steps of telomerase regulation were not affected by IM. This study demonstrates an additional cellular target of IM, not necessarily mediated via known tyrosine kinases, that causes inhibition of TA and cell proliferation.
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PMID:Imatinib mesylate (Gleevec) downregulates telomerase activity and inhibits proliferation in telomerase-expressing cell lines. 1587 Jul 11

Inactivation of p15(Ink4b) expression by promoter hypermethylation occurs in up to 80% of acute myeloid leukemia (AML) cases and is particularly common in the FAB-M2 subtype of AML, which is characterized by the presence of the RUNX1-ETO translocation in 40% of cases. To establish whether the loss of p15(Ink4b) contributes to AML progression in association with RUNX1-ETO, we have expressed the RUNX1-ETO fusion protein from a retroviral vector in hematopoietic progenitor cells isolated from wild-type, p15(Ink4b) or p16(Ink4a) knockout bone marrow. Analysis of lethally irradiated recipient mice reconstituted with RUNX1-ETO-expressing cells showed that neither p15(Ink4b) or p16(Ink4a) loss significantly accelerated disease progression over the time period of one year post-transplantation. Loss of p15(Ink4b) alone resulted in increased myeloid progenitor cell frequencies in bone marrow by 10-month post-transplant and a 19-fold increase in the frequency of Lin(-)c-Kit(+)Sca-1(+) (LKS) cells that was not associated with expansion of long-term reconstituting HSC. These results strongly suggest that p15(Ink4b) loss must be accompanied by additional oncogenic changes for RUNX1-ETO-associated AML to develop.
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PMID:Roles of p15Ink4b and p16Ink4a in myeloid differentiation and RUNX1-ETO-associated acute myeloid leukemia. 1803 85


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