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

The hallmark of chronic myelogenous leukemia is the translocation of the human c-abl protooncogene (ABL) from chromosome 9 to the specific breakpoint cluster region (bcr) of the BCR gene on chromosome 22. The t(9;22)(q34;q11) translocation results in the formation of a BCR-ABL fusion gene that encodes a 210-kDa chimeric protein with abnormal tyrosine kinase activity. The ABL and BCR genes are expressed by normal cells and thus the encoded proteins are presumably nonimmunogenic. However, the joining-region segment of the p210BCR-ABL chimeric protein is composed of unique sequences of ABL amino acids joined to BCR amino acids that are expressed only by malignant cells. The current study demonstrates that the joining region of BCR-ABL protein is immunogenic to murine T cells. Immunization of mice with synthetic peptides corresponding to the joining region elicited peptide-specific, CD4+, class II major histocompatibility complex-restricted T cells. The BCR-ABL peptide-specific T cells recognized only the combined sequence of BCR-ABL amino acids and not BCR or ABL amino acid sequences alone. Importantly, the BCR-ABL peptide-specific T cells could recognize and proliferate in response to p210BCR-ABL protein. The response of peptide-specific T cells to protein demonstrated that p210BCR-ABL can be processed by antigen-presenting cells so that the joining segment is bound to class II major histocompatibility complex molecules in a configuration similar to that of the immunizing peptide and in a concentration high enough to stimulate the antigen-specific T-cell receptor. Thus, BCR-ABL protein represents a potential tumor-specific antigen related to the transforming event and shared by many individuals with chronic myelogenous leukemia.
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PMID:T-cell immunity to the joining region of p210BCR-ABL protein. 134 32

The effects of various compounds which modulated the intracellular signal transduction on the induction of class I major histocompatibility complex (MHC) antigens by recombinant human interferon-gamma (rIFN-gamma) were investigated using K562, chronic myelogenous leukemia cells. Class I or class II MHC antigens were not expressed in untreated K562 cells and rIFN-gamma (600 units/ml) weakly induced class I antigens on the cells. Among the compounds tested, verapamil but not the calcium ionophore A23187 enhanced the rIFN-gamma-induced class I antigen expression at both the surface molecule and mRNA levels and enhancement by verapamil occurred in a dose-dependent manner at non-toxic concentrations examined (approximately 50 microM). Verapamil alone had no inducible effect on MHC antigen expression. Deprivation of Ca2+ in culture medium by ethylene glycol-bis(beta-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA) could not cause an enhancement of class I antigen induction by rIFN-gamma. Simultaneous exposure of K562 cells to rIFN-gamma (600 units/ml) and recombinant human tumor necrosis factor (rTNF; 1000 units/ml) in combination with verapamil (50 microM) resulted in a further increase of class I antigens in the cells. The expressions of c-myc oncogene in K562 cells were not changed when the cells were treated with rIFN-gamma (600 units/ml) or verapamil (50 microM), either alone or in combination. These results indicate that verapamil synergistically interacts with rIFN-gamma on the class I antigen induction in K562 cells irrespective of c-myc gene expression and that class I antigen induction in this cell line may not be relevant to calcium influx triggered by IFN-gamma.
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PMID:Effect of verapamil on the class I major histocompatibility complex antigen expression in K562 chronic myelogenous leukemia cells treated with recombinant human interferon-gamma. 151 24

We studied the in vitro effects of lymphokine-activated killer (LAK) cells from the peripheral blood of chronic myeloid leukemia (CML) patients after allogeneic and syngeneic bone marrow transplantation (BMT). LAK cells were generated by incubating peripheral blood mononuclear cells from patients post-BMT with recombinant interleukin-2 (IL-2) (500 U/mL) in 10% AB serum for 7 days. They were phenotyped and tested for activity in a standard 4-hour 51Cr release assay (n = 37) and in a CFU-GM assay (n = 24). We found that the LAK cells were mainly activated natural killer cells, but some were CD3+ T cells. In the 51Cr release assay LAK cells from 20 of 33 (61%) allogeneic and 2 of 4 syngeneic recipients killed recipient CML cells and in 22 of 37 (60%) cases also killed the HLA disparate CML cells. In the CFU-GM assay the LAK cells incubated together with the CML cells in liquid culture before plating inhibited (P less than .05) colony growth in 16 of 22 allogeneic and 2 of 2 syngeneic recipients. Cell-cell contact was necessary for optimal effect. There was little or no inhibition of proliferation of donor marrow CFU-GM. This in vitro graft-versus-leukemia (GVL) effect could also be demonstrated after LAK effectors were depleted of CD3+ T cells. It was inducible in recipients of both T cell-depleted and T cell-replete donor marrow and in recipients with or without graft-versus-host disease. These results suggest that a major histocompatibility complex-unrestricted GVL effect is inducible following allogeneic and syngeneic BMT. The use of IL-2/LAK cells after BMT could reduce the risk of relapse.
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PMID:Induction of in vitro graft-versus-leukemia activity following bone marrow transplantation for chronic myeloid leukemia. 224 25

The immune response of bone allografts has not been well understood. The present study was performed to examine the MLC response, CML activity, and alloantibody production of inbred mice receiving fresh and frozen bone allografts. A) Fresh allografts: High MLC response was observed in an early phase of the culture, suggesting the activation and proliferation of helper T cells. Percent cytotoxicity of CML assay was 24% on the 9th day after grafting, indicating the production of cytotoxic T cells. High alloantibody titer was observed on the 30th day after grafting, further indicating the production of the cytotoxic alloantibody. B) Frozen allografts: No significant difference was observed between frozen allografts and fresh isografts (control group) in these immunological responses. These results indicated that the antigenicity of the frozen bone decreased greatly so that matching of the major histocompatibility complex may not be required.
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PMID:[Study on the immune response of mice receiving bone allografts]. 296 43

A patient with Philadelphia chromosome (Ph) chronic myelogenous leukemia (CML), in chronic phase, was treated with recombinant gamma-interferon (r gamma-IFN) in a phase I clinical trial. Prior to treatment, analysis of in vitro agar culture parameters indicated hyporesponsiveness of granulocyte-macrophage colony-forming cells (CFU-GM) to inhibition by prostaglandin E and acidic isoferritins and diminished expression of class II major histocompatibility complex (MHC) antigens (HLA-DR). Treatment was associated with no change in bone marrow cellularity or in the percentage of Ph cells. However, in vitro cultures of bone marrow cells showed a return to normal levels of both expression of CFU-GM class II antigen and of sensitivity to inhibition by prostaglandin E and acidic isoferritins which predicted and/or confirmed clinical response. Throughout the course of interferon therapy, white blood cell counts (WBC) and the percentage of bone marrow blast cells were maintained at normal levels. Onset of aggressive-phase disease was associated with increased WBC, an increase in bone marrow blast cells, a secondary chromosomal abnormality, loss of CFU-GM sensitivity to inhibition by putative negative growth regulators, and markedly diminished MHC class II antigen expression. Following a bone marrow transplant from a matched sibling, all hematologic parameters studied were found to be normal. These findings indicate that treatment with r gamma-IFN can modulate some of the abnormal growth characteristics of CFU-GM observed in CML.
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PMID:Modulation of responsiveness of chronic myelogenous leukemia granulocyte-macrophage colony-forming cells to growth regulation following in vivo treatment with recombinant gamma-interferon. 313 Jul 50

Human leukocyte antigen-DP (HLA-DP) typing was performed on patients with chronic myelogenous leukemia (CML, n = 44), acute nonlymphoblastic leukemia (ANLL, n = 34), or acute lymphoblastic leukemia (ALL, n = 41). Frequencies of DPw alleles in CML and ANLL patients were not significantly different from 254 controls, except that in ANNL DPw1 was absent. This was most likely due to the concurrent absence of DR3 with which DPw1 is in linkage. In contrast, in ALL, frequencies of DPw2 and DPw5 were significantly increased (corrected P less than 0.05, relative risk (RR) = 2.19 and corrected P less than 0.01, RR = 6.92, respectively). This was not due to linkage with DR. The frequency of DPw1 also tended to be reduced, but this was not caused by a similar decrease of DR3 in ALL. These results, therefore, demonstrate both positive and negative associations between major histocompatibility complex (MHC) gene products which are in only very weak linkage with the rest of HLA, and acute lymphocytic, but neither acute nor chronic myelogenous, leukemias. The HLA-DP region could thus contain long sought-after genes influencing susceptibility and resistance to leukemogenesis.
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PMID:Human leukocyte antigen-DP in leukemia. 342 71

Defective natural killer (NK) cell populations from patients with chronic myelogenous leukemia (CML), that reacted with both HNK-1+ and B73.1+ antibodies, were obtained by a fluorescence-activated cell sorter (FACS). These fractions, along with NK fractions from normal donors which reacted with both antibodies, were expanded as bulk cultures or clones by limiting dilution, for 4 weeks in the presence of 10% interleukin 2 (IL 2), human type AB plasma, and irradiated human allogeneic mononuclear cells. Successfully established clones from patients with CML, with lytic activity against autologous and more differentiated neoplastic granulocytes, were generated more efficiently from B73.1+ than from HNK-1+ subsets. However, there were no significant differences among the generations of B73.1+ and HNK-1+ clones for both patients and normal donors with lytic activity against NK susceptible K-562 targets. Fresh myeloblast preparations from a blast crisis were found to be more susceptible to lysis by IL 2-proliferative B73.1+ and HNK-1+ clones than were fresh myelocyte preparations from a chronic phase CML patient, which were lytically susceptible to only B73.1+ clones. B73.1+ and HNK-1+ subsets from CML patients demonstrated major histocompatibility complex nonrestricted killing, and showed the following predominant phenotypes: B73.1+T3+T8+ or B73.1+T3+T8- from B73.1+ subsets; and HNK-1-T3+T8+ (initially HNK-1+) from HNK-1+ subsets. In contrast, B73.1+ and HNK-1+ clones from normal donors showed the following predominant phenotypes: B73.1+T3-T8-; and HNK-1-T3-T8- or HNK-1-T3-T8+ (initially all HNK-1+). Short-term in vitro IL 2 or interferon treatment of fresh NK defective subsets from CML patients resulted in minimal cytotoxic augmentation. In contrast, defective NK cells from CML patients, whether HNK-1+ or B73.1+ subsets, proliferated with complete regeneration of cytolytic activity after a 3-4 week exposure to IL 2, but differed in phenotypic profiles as compared to those of normal donors. These observations imply that not only fresh defective NK cells but also the cytotoxically restored clones from CML patients are derived from different NK subsets and may represent undifferentiated forms of NK cells that may be arrested at an early stage of development by yet unknown mechanism(s). In vitro substantiation of autologous leukemia cell killing by IL 2-proliferative NK cell clones is encouraging and may allow for new in vivo immunotherapeutic modalities in CML patients.
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PMID:Natural killer (NK) cell immunodeficiency in patients with chronic myelogenous leukemia. II. Successful cloning and amplification of natural killer cells. 349 52

The relative contributions made by the major class I (RT1.A) and class II (RT1.B) antigens of the rat major histocompatibility complex (MHC) to the immunogenicity of corneal and skin allografts were investigated using congenic animals. PVG (RT1c) recipients were given skin or heterotopic cornea grafts from congenic PVG.1A (RT1a) or PVG.R1 (RT1r1) donors, which respectively share the entire RT1 complex or only the RT1.A (major class I MHC antigen) region with fully allogeneic ACI (RT1a) rats. Recipient splenocytes were tested at ten days posttransplant for their ability to lyse ACI, PVG.1A, PVG.R1, and PVG target cells in a secondary CML following 6 days in vitro stimulation with irradiated ACI spleen cells. Effector cells from PVG recipients of both RT1.A and B disparate (PVG.1A donor) and RT1.A disparate (PVG.R1) skin or cornea grafts lysed ACI, PVG.1A, and PVG.R1 (but not PVG) targets at levels significantly above controls given syngeneic grafts. However, the level of cytotoxicity against PVG.R1 as well as ACI and PVG.1A allogeneic targets was always significantly higher following PVG.1A grafts than following PVG.R1 grafts, indicating that the addition of a class II MHC antigen difference markedly augmented the immunogenicity of class I MHC antigen disparate cornea and skin grafts. Taken together with other recent evidence confirming the presence of Langerhans cells in the normal rat (and human) cornea, these results suggest that class II MHC-bearing cells make an important contribution to the immunogenicity of corneal allografts.
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PMID:Relative contribution of major histocompatibility complex antigens to the immunogenicity of corneal allografts. 351 52

Human B and T lymphocytes from a panel of healthy individuals were tested against serial dilutions of 68 mare, 81 cow, 7 sow, and 87 ewe sera. All the animals had been alloimmunized by pregnancies and/or blood transfusions. Weak correlations with HLA-A, B, C, and DR specificities were found in 20 sera. Twelve other sera, 9 from ewes and 3 from cows, had a strong reactivity against T lymphocytes but weak or no reactivity against B cells, spleen null cells, granulocytes, and platelets, suggesting a non-major histocompatibility complex (MHC) cross-reactivity. They were cytotoxic for most of the cells of malignant proliferative origin tested thus far, including T acute lymphoblastic leukemia (T ALL), common ALL (cALL), acute myeloblastic leukemia (AML), and Sezary cells, but were negative with B lymphoblastoid cell lines and cells from patients with B chronic lymphocytic leukemia (CLL) and chronic myelocytic leukemia (CML). The hypothesis that humans and certain other mammals share a common determinant on T-lineage cells and some malignant cells is advanced.
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PMID:Selective reactivity of sera from alloimmunized sheep and cattle against human T and leukemia cells. 698 19

Between August 1985 and July 1994, we performed 115 volunteer unrelated donor (VUD) bone marrow transplants (BMT) for first chronic phase (n = 86) or advanced phase (n = 29) chronic myeloid leukemia (CML). Standard serologic HLA typing of potential donors and recipients was supplemented with one-dimensional isoelectric focusing (IEF) for class I proteins, allogenotyping for DR and DQ alleles using DNA restriction fragment length polymorphism (RFLP) analysis, and the measurement of antirecipient major histocompatibility complex (MHC) cytotoxic T-lymphocyte precursor cells in the donors' blood (CTLp assay). Recipients were conditioned for transplantation with a combination of high-dose chemotherapy and total body irradiation (n = 103) or high-dose chemotherapy alone (n = 12). Twenty eight recipients received ex vivo T-cell-depleted marrow, and 84 underwent some form of in vivo T-cell depletion. The probability of severe (grades III or IV) acute graft-versus-host disease (aGVHD) was 24%, and that of extensive chronic graft-versus-host disease (cGVHD), 38%. Proportional hazards regression analysis showed an association between low frequency CTLp and a reduced incidence of severe aGVHD (relative risk [RR], 0.28; P = .0035). The probability of relapse at 3 years was 23%, with first chronic phase disease being independently associated with a lower risk of relapse (RR, 0.71; P = .01). The overall leukemia-free survival (LFS) at 3 years was 37%; the LFS for the first chronic phase and advanced phase recipients was 41% and 26%, respectively. First chronic phase disease (RR, 0.56; P = .063) and the combination of recipient cytomegalovirus (CMV) seronegativity and an IEF-matched donor (RR, 0.48; P = .011) were both associated with improved LFS. The probabilities of survival and LFS for patients under 40 years of age transplanted in first chronic phase from an IEF-matched donor were 73% and 50%, respectively. We conclude that VUD BMT is a reasonable option for patients with CML; when using ex vivo or in vivo T-cell depletion, optimal results are achieved in patients transplanted in chronic phase with marrow from donors without demonstrable class I HLA mismatch and a low CTLp frequency.
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PMID:Bone marrow transplantation for chronic myeloid leukemia with volunteer unrelated donors using ex vivo or in vivo T-cell depletion: major prognostic impact of HLA class I identity between donor and recipient. 757 68


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