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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of CXCL12 in the bone marrow (BM) homing and growth of B-cell progenitor acute lymphoblastic leukemia (ALL) has been established. However, the effect of modulating CXCL12/CXCR4 interactions on the retention of ALL cells within the supportive BM microenvironment and the expansion and dissemination of ALL cells in vivo has not been examined. We used mouse models of human childhood and murine leukemia and specific peptide and small molecule CXCR4 antagonists to examine the importance of CXCL12/CXCR4 in the development of leukemia in vivo. CXCR4 antagonists mobilized ALL cells into the peripheral blood (PB). Extended administration of CXCR4 antagonists to mice with leukemia resulted in a reduction in the number of leukemic cells in the PB and spleens of animals compared to control treated animals in three of the five cases tested. There was also a marked reduction in the dissemination of ALL cells to extramedullary sites including liver and kidney in all cases where this occurred. Considering the inhibitory effect of stromal layers on the activity of chemotherapeutic agents and the interactive effect of CXCL12 antagonists with chemotherapeutic agents in vitro, this raises the possibility of using these agents to potentiate the effects of current chemotherapy regimens.
Leukemia 2007 Jun
PMID:CXCR4 antagonists mobilize childhood acute lymphoblastic leukemia cells into the peripheral blood and inhibit engraftment. 1741 Jan 86

Chemokine (C-X-C motif) receptor 4 (CXCR4) is essential for homing and maintenance of haematopoietic stem cells in distinct stromal cell niches within the marrow. Chemotactic responsiveness of haematopoietic stem cells is restricted to the ligand for CXCR4, stromal cell-derived factor-1 (SDF-1/CXCL12), which is constitutively secreted by marrow stromal cells. Myeloid and lymphoid leukaemia cells also express CXCR4 that induces leukaemia cell chemotaxis and migration beneath marrow stromal cells. CXCR4 expression levels have a major prognostic impact in acute myeloid leukaemia. There is growing in vitro and in vivo evidence that CXCR4 expression by leukaemia cells allows for homing and their retention within the marrow. As such, leukaemia cells appear to utilise CXCR4 to access niches that are normally restricted to progenitor cells, and thereby reside in a microenvironment that favours their growth and survival. CXCR4- and integrin-mediated contact between leukaemia cells and stromal cells protects leukaemia cells from spontaneous and chemotherapy-induced cell death and therefore may represent a mechanism to explain minimal residual disease and subsequent relapses commonly seen in the treatment of these diseases. This review summarises our current knowledge regarding the importance of CXCR4 in acute and chronic leukaemia, discusses the importance of CXCR4 detection by flow cytometry in the diagnostic workup of leukaemia patients, and introduces the potential role of CXCR4-targeting compounds for the treatment of leukaemia patients.
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PMID:The CXCR4 chemokine receptor in acute and chronic leukaemia: a marrow homing receptor and potential therapeutic target. 1745 52

Hematopoietic stem/progenitor cells (HSC/P) reside in the bone marrow in distinct anatomic locations (niches) to receive growth, survival and differentiation signals. HSC/P localization and migration between niches depend on cell-cell and cell-matrix interactions, which result from the cooperation of cytokines, chemokines and adhesion molecules. The CXCL12-CXCR4 pathway, in particular, is essential for myelopoiesis and B lymphopoiesis but the molecular mechanisms of CXCL12 action remain unclear. We previously noted a strong correlation between prolonged CXCL12-mediated focal adhesion kinase (FAK) phosphorylation and sustained pro-adhesive responses in progenitor B cells, but not in mature B cells. Although FAK has been well studied in adherent fibroblasts, its function in hematopoietic cells is not defined. We used two independent approaches to reduce FAK expression in (human and mouse) progenitor cells. RNA interference (RNAi)-mediated FAK silencing abolished CXCL12-induced responses in human pro-B leukemia, REH cells. FAK-deficient REH cells also demonstrated reduced CXCL12-induced activation of the GTPase Rap1, suggesting the importance of FAK in CXCL12-mediated integrin activation. Moreover, in FAK(flox/flox) hematopoietic precursor cells, Cre-mediated FAK deletion resulted in impaired CXCL12-induced chemotaxis. These studies suggest that FAK may function as a key intermediary in signaling pathways controlling hematopoietic cell lodgment and lineage development.
Leukemia 2007 Aug
PMID:Focal adhesion kinase is required for CXCL12-induced chemotactic and pro-adhesive responses in hematopoietic precursor cells. 1756 20

Local breast radiation therapy (RT) is associated with a 3-fold increased risk of secondary acute myeloid leukemia. As a first step in determining the mechanism(s) underlying this observation, we investigated the role of RT in mediating the active recruitment of hematopoietic stem cells (HSC) to the site of RT. Our results show in a mouse model that local RT delivered to the left leg causes preferential accumulation of bone marrow mononuclear cells to the irradiated site, with maximum signal intensity observed at 7 days post-RT. This is associated with a 4-fold higher number of donor-derived HSC present in the left leg, demonstrating recruitment of HSC to the site of RT. SDF-1, matrix metalloproteinase 2 (MMP-2), and MMP-9 expression is significantly increased in the irradiated bone marrow, and their inhibition significantly reduced HSC recruitment to the irradiated bone marrow. Our data show that local RT has significant systemic effects by recruiting HSC to the irradiated bone marrow site, a process mediated by SDF-1, MMP-2, and MMP-9. These results raise the possibility that the exposure of increased numbers of HSC at a local site to fractionated irradiation may increase the risk of leukemogenesis. Our data also suggest some opportunities for leukemia prevention in breast cancer patients undergoing RT.
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PMID:Local radiotherapy induces homing of hematopoietic stem cells to the irradiated bone marrow. 1797 51

DPP IV/CD26 contributes to cell signalling by various mechanisms: as a receptor or co-receptor, as a component of a membrane-associated signal transduction complex and by virtue of its exopeptidase activity. The presence of enzymatically active DPP IV in a variety of tissues and in plasma makes it challenging to review clinical consequences of chemokine turnover by DPP IV activity, even more so in times when the concept of DPP IV inhibition for therapeutic purposes has reached the stage of clinical application. Among the known substrates of DPP IV/CD26, Stromal cell-derived factor 1 (SDF-1, CXCL12) has gained attention in recent years as a critical mediator of chemotaxis and tissue invasion, especially in the context of malignant disease. SDF-1 and its receptor, CXCR4, differ from other chemokines and their respective receptors by a lack of redundancy and pleiotropism. Therapeutic intervention using CXCR4 antagonists has been proposed. It seems appropriate to review the role of SDF-1 in haematopoiesis and its malignant counterpart, leukaemia, and to assess the interference of DPP IV/CD26 with the SDF-1/CXCR4 axis as well as possible risks and benefits of DPP IV inhibition.
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PMID:SDF-1 (CXCL12) in haematopoiesis and leukaemia: impact of DPP IV/CD26. 1798 66

Bone marrow engraftment in the context of hematopoietic stem cell and progenitor (HSC/P) transplantation is based on the ability of intravenously administered cells to lodge in the medullary cavity and be retained in the appropriate marrow space, a process referred to as homing. It is likely that homing is a multistep process, encompassing a sequence of highly regulated events that mimic the migration of leukocytes to inflammatory sites. In leukocyte biology, this process includes an initial phase of tethering and rolling of cells to the endothelium via E- and P-selectins, firm adhesion to the vessel wall via integrins that appear to be activated in an "inside-out" fashion, transendothelial migration, and chemotaxis through the extracellular matrix (ECM) to the inflammatory nidus. For HSC/P, the cells appear to migrate to the endosteal space of the bone marrow. A second phase of engraftment involves the subsequent interaction of specific HSC/P surface receptors, such as alpha(4)beta(1) integrin receptors with vascular cell-cell adhesion molecule-1 and fibronectin in the ECM, and interactions with growth factors that are soluble, membrane, or matrix bound. We have utilized knockout and conditional knockout mouse lines generated by gene targeting to study the role of Rac1 and Rac2 in blood cell development and function. We have determined that Rac is activated via stimulation of CXCR4 by SDF-1, by adhesion via beta(1) integrins, and via stimulation of c-kit by the stem cell factor-all of which involved in stem cell engraftment. Thus Rac proteins are key molecular switches of HSC/P engraftment and marrow retention. We have defined Rac proteins as key regulators of HSC/P cell function and delineated key unique and overlapping functions of these two highly related GTPases in a variety of primary hematopoietic cell lineages in vitro and in vivo. Further, we have begun to define the mechanisms by which each GTPase leads to specific functions in these cells. These studies have led to important new understanding of stem cell bone marrow retention and trafficking in the peripheral circulation and to the development of a novel small molecule inhibitor that can modulate stem cell functions, including adhesion, mobilization, and proliferation. This chapter describes the biochemical footprint of stem cell engraftment and marrow retention related to Rho GTPases. In addition, it reviews abnormalities of Rho GTPases implicated in human immunohematopoietic diseases and in leukemia/lymphoma.
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PMID:Rho GTPases and regulation of hematopoietic stem cell localization. 1837 78

Berberine plays a prominent role on the control of tumor cell invasion and migration. SDF-1 is a homeostatic chemokine that signals through CXCR4 which is expressed by hematopoietic tumor cells. The SDF-1/CXCR4 axis is involved in the migration process of leukemic cells. In this study, we investigated the effects of berberine on the SDF-1-induced HL-60 cells, primary acute myeloid leukemia (AML) cells and leukemic stem cells (LSCs) migration. Transwell migration chambers (8 microm) were used to assess the role of berberine on leukemic cell migration; Flow cytometry was used to analyze the role of berberine on the CXCR4 expression; SDF-1 protein level secreted by bone marrow stromal cells (BMSCs) was evaluated by ELISA. Results demonstrated that berberine could partly inhibit SDF-1-induced AML cells as well as LSCs migration. Berberine could reduce SDF-1 protein level secreted by BMSCs in the microenvironment but not affect CXCR4 expression on HL-60 cell membrane, and we hypothesized that berberine could inhibit AML cells migration partly by reducing the secreting of SDF-1 by BMSCs and inhibiting HERG1 K(+) channels of leukemic cells. Therefore, it is speculated that berberine might be a potentially effective agent for prevention of leukemia.
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PMID:Berberine inhibits SDF-1-induced AML cells and leukemic stem cells migration via regulation of SDF-1 level in bone marrow stromal cells. 1880 69

The CXCR4/SDF-1 axis has been studied extensively because of its role in development and hematopoiesis. In acute myeloid leukemia (AML), elevated expression of CXCR4 has been shown to correlate with shortened survival. Hy-poxia increases CXCR4 in several tumor models, but the impact of reduced O(2) partial pressure (pO(2)) on expression and biologic function of CXCR4 in AML is unknown. We determined pO(2) in bone marrows of AML patients as 6.1% (+/-1.7%). At this pO(2), CXCR4 surface and total expression were up-regulated within 10 hours in leukemic cell lines and patient samples as shown by Western blotting, fluorescence-activated cell sorting, and microscopy. Interestingly, hypoxic cells failed to internalize CXCR4 in response to SDF-1, and upon reoxygenation at 21% O(2), surface and total expression of CXCR4 rapidly decreased independent of adenosine triphosphate or proteasome activity. Instead, increased pO(2) led to alteration of lipid rafts by cholesterol depletion and structural changes and was associated with increased shedding of CXCR4-positive microparticles, suggesting a novel mechanism of CXCR4 regulation. Given the importance of CXCR4 in cell signaling, survival, and adhesion in leukemia, the results suggest that pO(2) be considered a critical variable in conducting and interpreting studies of CXCR4 expression and regulation in leukemias.
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PMID:CXCR4 expression and biologic activity in acute myeloid leukemia are dependent on oxygen partial pressure. 1895 86

Exposure to ionizing radiation is a well-known risk factor for a number of human cancers, including leukemia and thyroid cancer. It has been known for a long time that exposure of cells to radiation results in extensive DNA damage; however, a small number of studies have tried to explain the mechanisms of radiation-induced carcinogenesis. The high prevalence of RET/PTC rearrangements in patients who have received external radiation, and the evidence of in vitro induction of RET rearrangements in human cells, suggest an enhanced sensitivity of the RET genomic region to damage by ionizing radiation. To assess whether RET is indeed more sensitive to radiations than other genomic regions, we used a COMET assay coupled with fluorescence in situ hybridization, which allows the measurement of DNA fragmentation in defined genomic regions of single cells. We compared the initial DNA damage of the genomic regions of RET, CXCL12/SDF1, ABL, MYC, PLA2G2A, p53, and JAK2 induced by ionizing radiation in both a lymphoblastoid and a fetal thyroid cell line. In both cell lines, RET fragmentation was significantly higher than in other genomic regions. Moreover, a differential distribution of signals within the COMET was associated with a higher percentage of RET fragments in the tail. RET was more susceptible to fragmentation in the thyroid-derived cells than in lymphoblasts. This enhanced susceptibility of RET to ionizing radiation suggests the possibility of using it as a radiation exposure marker.
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PMID:Enhanced sensitivity of the RET proto-oncogene to ionizing radiation in vitro. 1897 43

Hematopoietic and epithelial cancer cells express CXCR4, a seven-transmembrane G-protein-coupled chemokine receptor. Stromal cells within the bone marrow microenvironment constitutively secrete stromal cell-derived factor-1 (SDF-1/CXCL12), the ligand for CXCR4. Activation of CXCR4 induces leukemia cell trafficking and homing to the marrow microenvironment, where CXCL12 retains leukemia cells in close contact with marrow stromal cells that provide growth and drug resistance signals. CXCR4 antagonists, such as Plerixafor (AMD3100) and T140 analogs, can disrupt adhesive tumor-stroma interactions and mobilize leukemia cells from their protective stromal microenvironment, making them more accessible to conventional drugs. Therefore, targeting the CXCR4-CXCL12 axis is a novel, attractive therapeutic approach that is explored in ongoing clinical trials in leukemia patients. Initially, CXCR4 antagonists were developed for the treatment of HIV, where CXCR4 functions as a co-receptor for virus entry into T cells. Subsequently, CXCR4 antagonists were noticed to induce leukocytosis, and are currently used clinically for mobilization of hematopoietic stem cells. However, because CXCR4 plays a key role in cross-talk between leukemia cells (and a variety of other tumor cells) and their microenvironment, cancer treatment may become the ultimate application of CXCR4 antagonists. Here, we summarize the development of CXCR4 antagonists and their preclinical and clinical activities, focusing on leukemia and other cancers.
Leukemia 2009 Jan
PMID:CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers. 1898 63


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