Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A new human B lymphocyte membrane antigen, CB2, has been detected by a mouse monoclonal IgM antibody. CB2 appears to be predominantly expressed on normal and malignant cells expressing surface membrane immunoglobulin (SmIg). By indirect immunofluorescence, the number of CB2-positive cells in normal peripheral blood correlated well with the number of SmIg-positive cells. Cytotoxicity studies on isolated cell populations showed that CB2 was present on normal B cells isolated from the spleens of 52 donors and on peripheral blood B cells from 8 donors. Monocytes, T cells, granulocytes, platelets, and red cells were CB2 negative. Only malignant cells expressing SmIg were positive. These included B-CLL, B lymphoma, prolymphocytic leukemia, and B lymphoma cell lines Daudi, Raji, and Conception. SmIg-negative leukemia cells, such as common acute lymphoblastic leukemia, acute and chronic myelogenous leukemia, and T cell leukemias, were negative. Blocking studies with human immunoglobulin suggests that the CB2 antigen is not directed against immunoglobulin determinants. Immunoperoxidase studies on normal lymph node sections show that CB2-positive cells are predominantly present in the mantle region of the follicle, whereas B1-positive cells are mainly in the germinal center.
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PMID:A cytotoxic monoclonal antibody detecting a novel B cell membrane antigen expressed predominantly on cells bearing surface membrane immunoglobulin. 660 81

The role of glyoxal and glycolaldehyde in protein cross-linking and N epsilon-(carboxymethyl)lysine (CML) formation during Maillard reaction under physiological conditions was investigated. Incubation of bovine serum albumin with these reagents lead to rapid formation of C-2-imine cross-links and CML. Initial CML formation rate from glyoxal was not dependent on oxidation, suggesting an intramolecular Cannizzaro reaction. CML formation from glucose/lysine or Amadori product of both was strongly dependent on oxidation. Blocking of Amadori product by boric acid totally suppressed CML formation from Amadori product, but only by 37% in the glucose/lysine system. Trapping of glyoxal with aminoguanidine hardly suppressed CML formation from Amadori product, whereas it blocked 50% of CML production in the glucose/lysine system. While these results would support a significant role for glucose autoxidation in CML formation, the addition of lysine to a glucose/aminoguanidine incubation system catalyzed glyoxal-triazine formation 7-fold, thereby strongly suggesting that glucose autoxidation is not a factor for glyoxal-mediated CML formation. Based on these results, it can be estimated that approximately 50% of the CML forming in a glucose/lysine system originates from oxidation of Amadori product, and 40-50% originates from a pre-Amadori stage largely independent from glucose autoxidation. This step may be related to the so-called Namiki pathway of the Maillard reaction.
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PMID:Mechanism of protein modification by glyoxal and glycolaldehyde, reactive intermediates of the Maillard reaction. 773 Mar 3

The role of T lymphocytes in the control of chronic myeloid leukemia (CML) after bone marrow transplantations has been clearly shown. This effect closely correlates with graft-versus-host disease (GVHD). A specific graft-versus-leukemia (GVL) effect separate from GVHD has been postulated but has been difficult to show. One possible target for specific GVL activity is the bcr-abl fusion protein characteristic of CML. We have investigated the use of normal peptide-pulsed dendritic cells for the generation of cytotoxic, bcr-abl-specific T cells from normal donors. T cells (CD3+, CD8+, TCR alpha beta+, and NK receptor-negative) generated from a normal donor (HLA A24, B52, B59, Cw1) after stimulation with autologous dendritic cells, primed with a 16 mer peptide spanning the b3a2 breakpoint of bcr-abl, lysed CML cells from the peripheral blood of seven patients with CML with the b3a2 breakpoint. CML cells from four patients with only the b2a2 breakpoint were not lysed. Phytohemagglutinin (PHA) blasts derived from peripheral blood of patients with CML were not lysed, suggesting that cytotoxicity was not due to alloreactivity. Blocking experiments with anti-HLA-A,B,C indicated that cytotoxicity was dependent on recognition of major histocompatibility complex (MHC) class I molecules, although cytotoxicity was not MHC-restricted because not all patients shared HLA types with the T-cell donor. Specificity for bcr-abl and absence of alloreactivity was confirmed by the presence of lytic activity against autologous and allogeneic class I HLA-A matched monocytes pulsed with the 16 mer bcr-abl fusion peptide, but not against unpulsed monocytes or monocytes pulsed with other peptides. These results show that bcr-abl-specific T cells with marked cytotoxic activity against CML cells can be generated and amplified from normal donor peripheral blood. Recognition of HLA molecules is essential for cytotoxicity but strict HLA identity is not required.
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PMID:Dendritic cells stimulate the expansion of bcr-abl specific CD8+ T cells with cytotoxic activity against leukemic cells from patients with chronic myeloid leukemia. 944 59

Investigating the cellular effects of food compounds formed by heat treatment during processing, we recently demonstrated the expression of the receptor for advanced glycation endproducts (RAGE) and the p44/42 MAP kinase activation by casein-N(epsilon )-(carboxymethyl)lysine (casein-CML), a food-derived AGE, in the intestinal cell line Caco-2. In this work, we report a Caco-2 p44/42 MAP kinase activation by bread crust and coffee extract. After identification, quantification, and synthesis of two key compounds formed in association with the process-induced heat impact applied to bread dough and coffee beans, those compounds, namely the AGE pronyl-glycine and the non-AGE N-methylpyridinium, were also demonstrated for the first time to activate the p44/42 MAP kinase through binding to RAGE in Caco-2 cells. Blocking of RAGE by an antagonistic antibody and expression of C-terminally truncated RAGE resulted in a reduced Caco-2- and HEK-293-MAP kinase activation. These findings unequivocally point to a RAGE-mediated activating effect of chemically defined food-derived, thermally generated products, both, AGEs and non-AGEs, on cellular signal transduction pathways involved in inflammatory response and cellular proliferation.
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PMID:RAGE-mediated MAPK activation by food-derived AGE and non-AGE products. 1250 85

Chronic myelogenous leukaemia (CML) is one of the most intensively studied human malignancies. It has been the focus of major efforts to develop potent drugs for several decades, but until recently cure rates remained low. A breakthrough in CML therapy was very likely accomplished with the clinical introduction of STI-571 [imatinib mesylate; Gleevec (USA); Glivec (other countries)] in 2000/2001. Despite the hope that STI-571 has generated for many CML patients, development of resistance to this drug is already apparent in some cases, especially if the CML is diagnosed in its later stages. Therefore, novel drugs which can be used alone or in combination with STI-571 are highly desirable. This review briefly summarises the current understanding and therapy of CML and then discusses in more detail basic laboratory research that attempts to target Grb2, an adaptor protein known to directly interact with the Bcr portion of the Bcr-Abl fusion protein. Blocking the binding of Grb2 to the GDP-releasing protein SoS is well known to abrogate the activation of the GTPase Ras, a major driving force of the central mitogenic (MAP kinase) pathway. Additional Grb2 effector proteins may also contribute to the proliferation-inhibiting effects observed upon uncoupling Grb2 from its downstream signalling system. Since Grb2 is a known signal transducer for several major human oncogenes, this approach may have applications for a wider range of human cancers.
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PMID:High affinity molecules disrupting GRB2 protein complexes as a therapeutic strategy for chronic myelogenous leukaemia. 1268 10

Patients with blast crisis (BC) CML frequently become resistant to Imatinib, a Bcr-Abl tyrosine kinase-targeting agent. Eg5, a microtubule-associated motor protein has been described to be highly expressed in BC CML by microarray analysis (Nowicki et al., Oncogene 2003; 22:3952-63). We investigated the regulation of Eg5 by Bcr-Abl tyrosine kinase and its potential as a therapeutic target in BC CML. Eg5 was highly expressed in all Philadelphia chromosome positive (Ph(+)) cell lines and BC CML patient samples. Inhibition of Bcr-Abl by Imatinib downregulated Eg5 expression in Imatinib-sensitive KBM5 and HL-60p185 cells, but not in Imatinib-resistant KBM5-STI571, harboring a T315I mutation, and Bcr-Abl-negative HL-60 cells. Blocking Eg5 expression with antisense oligonucleotide (Eg5-ASO) or inhibiting its activity with the small-molecule Eg5 inhibitor, S-trityl-L-cysteine induced G(2)/M cell cycle block and subsequent cell death in both Imatinib-sensitive and -resistant cells. Further, Eg5-ASO treatment of SCID mice harboring KBM5 cell xenografts significantly prolonged the median survival of the animals (p = 0.03). Our findings suggest that Eg5 is downstream of and regulated by Bcr-Abl tyrosine kinase in Philadelphia chromosome positive cells. Inhibition of Eg5 expression or its activity blocks cell cycle progression and induces cell death independent of the cellular response to Imatinib. Therefore, Eg5 could be a potential therapeutic target for the treatment of BC CML, in particular Imatinib-resistant BC CML.
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PMID:Regulation and targeting of Eg5, a mitotic motor protein in blast crisis CML: overcoming imatinib resistance. 1696 80

Chronic myelogenous leukemia (CML) results from the transformation of a primitive hematopoietic cell by the BCR/ABL gene. BCR/ABL signaling has been studied in cell lines and murine models, but the transforming effects of BCR/ABL are highly dependent on cellular context, and mechanisms responsible for the transformation of primitive human hematopoietic cells remain poorly understood. Current targeted therapies fail to eliminate malignant CML progenitors, and improved understanding of crucial molecular mechanisms of progenitor transformation may facilitate the development of improved therapeutic approaches. We investigated the role of BCR/ABL tyrosine 177 (BCR/ABL-Y177) in CML progenitor transformation by comparing the effects of expression of Y177-mutated BCR/ABL, wild-type BCR/ABL, or green fluorescent protein alone on normal CD34(+) cells. We show that BCR/ABL-Y177 plays a critical role in CML progenitor expansion, proliferation, and survival. BCR/ABL expression results in enhanced Ras and Akt activity but reduced mitogen-activated protein kinase activity in human hematopoietic cells, which is reversed by BCR/ABL-Y177 mutation. Blocking BCR/ABL-Y177-mediated signaling enhances targeting of CML progenitors by imatinib mesylate. Our studies indicate that BCR/ABL-Y177 plays an essential role in Ras and Akt activation and in human hematopoietic progenitor transformation in CML.
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PMID:BCR-tyrosine 177 plays an essential role in Ras and Akt activation and in human hematopoietic progenitor transformation in chronic myelogenous leukemia. 1763 18

The BCR-ABL-fusion gene is critical for the development of chronic myeloid leukemia (CML) and BCR-ABL positive acute lymphatic leukemia (Ph+ ALL). Blocking BCR-ABL by the ABL tyrosine kinase inhibitor imatinib mesylate (IM, Gleevec) is clinically highly efficient. Treatment response is unfortunately compromised by the emergence of IM resistance, which is regularly seen in accelerated and blastic phase of CML (CML-AP/BP) and in Ph+ ALL. BCR-ABL kinase domain mutations are then considered the causative mechanism of IM resistance, because 50-60% of the IM resistant patients harbour such mutations. In contrast, IM resistance arises very rarely in patients that are treated with IM in early chronic phase of CML. This implies that BCR-ABL independent factors such as the cellular context of BCR-ABL expression and stage of disease decisively control the evolution of IM resistance. In line with this, novel Abl-kinase inhibitors such as dasatinib (DA) or nilotinib (NI) - although capable of inhibiting most of the BCR/-BL kinase mutants - still often fail to overcome resistance and do mostly not induce durable cytogenetic responses in IM resistant CML-AP/BC and Ph+ ALL patients. On the basis of available evidence it is proposed here that alternative genetic aberrations, which synergize with BCR-ABL to enable leukemic self-renewal are of causal importance for the evolution of clinical kinase inhibitor resistance. Kinase mutations may in turn reflect clonal variants of cells that emerge on the basis of an already existing IM resistant and self-renewing leukemic cell population. This model has clinical implications as it implies that even highly potent Abl-kinase inhibition can not target the genetic basis of IM resistance and will also not resolve the problem of Abl-kinase inhibitor resistance.
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PMID:Roots of imatinib resistance: a question of self-renewal? 1768 77

Patients with chronic myeloid leukemia who become resistant to the Abl kinase inhibitor imatinib can be treated with dasatinib. This sequential treatment can lead to BCR-ABL mutations conferring broad resistance to kinase inhibitors. To model the evolution of resistance, we exposed the mouse DA1-3b BCR-ABL(+) leukemic cell line to imatinib for several months, and obtained resistant cells carrying the E255K mutation. We then exposed these cells to dasatinib, and obtained dasatinib-resistant cells with composite E255K+T315I mutations. Subcloning isolated a minor clone also carrying V299L. In co-culture, mutated cells were able to spread resistance to non-mutated cells through overexpression of interleukin 3, activation of MEK/ERK and JAK2/STAT5 pathways, and downregulation of Bim. Even the presence of less than 10% of mutated cells was sufficient to protect non-mutated cells. Blocking JAK2 and MEK1/2 inhibited the protective effect of co-culture. Mutated cells were also sensitive to JAK2 inhibition, but blocking MEK1/2 alone, or in association with kinase inhibitors, had little effect. These data indicate that sequential Abl kinase inhibitor therapy can generate sub-populations of mutated cells, which may coexist with non-mutated cells and protect them through a paracrine mechanism. Targeting JAK2 could eliminate both populations.
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PMID:BCR-ABL mutants spread resistance to non-mutated cells through a paracrine mechanism. 1821 68

Chronic myeloid leukemia (CML) is a malignant myeloproliferative disease with a characteristic chronic phase (cp) of several years before progression to blast crisis (bc). The immune system may contribute to disease control in CML. We analyzed leukemia-specific immune responses in cpCML and bcCML in a retroviral-induced murine CML model. In the presence of cpCML and bcCML expressing the glycoprotein of lymphocytic choriomeningitis virus as a model leukemia antigen, leukemia-specific cytotoxic T lymphocytes (CTLs) became exhausted. They maintained only limited cytotoxic activity, and did not produce interferon-gamma or tumor necrosis factor-alpha or expand after restimulation. CML-specific CTLs were characterized by high expression of programmed death 1 (PD-1), whereas CML cells expressed PD-ligand 1 (PD-L1). Blocking the PD-1/PD-L1 interaction by generating bcCML in PD-1-deficient mice or by repetitive administration of alphaPD-L1 antibody prolonged survival. In addition, we found that PD-1 is up-regulated on CD8(+) T cells from CML patients. Taken together, our results suggest that blocking the PD-1/PD-L1 interaction may restore the function of CML-specific CTLs and may represent a novel therapeutic approach for CML.
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PMID:Programmed death 1 signaling on chronic myeloid leukemia-specific T cells results in T-cell exhaustion and disease progression. 1969 8


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