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)

Possible immunogenic heterogeneity of the HLA-Bw44 antigen was investigated using cytotoxic T lymphocytes (CTL) generated between donors identical for HLA-A2,3,-B7,w44. Highly discriminatory CTL combinations were identified that defined two subgroups of Bw44, designated 44.1 and 44.2. Out of 47 Bw44-positive donors tested in a population study, 30 were lysed by the CTL defining 44.1, and 19 were lysed by the CTL defining 44.2. All Bw44 cells could be typed as either 44.1 or 44.2, except two Bw44-positive cells that were phenotypically homozygous for the serologically defined Bw44 antigen and were lysed by both CTL. No Bw44-negative donors (zero out of 37) expressed either 44.1 or 44.2, although cold target blocking was required to eliminate a contaminating reactivity of one CTL population on Bw35 and some Bw45 cells. CTL were also raised between responder/stimulator combinations mismatched for Bw44. These CTL lysed all Bw44-positive target cells, indicating a CML antigen shared by all Bw44 cells. But clear discrimination of the 44.1 and 44.2 subgroups was obtained when appropriate cold target blocking cells were added. All donors with 44.2 expressed high levels of serologically detectable Bw44 on their platelets, and all with 44.1 expressed low levels (p less than 0.005). Furthermore, population studies indicate that 44.1 is in positive linkage disequilibrium with HLA-A2 and possibly DR4, whereas 44.2 is in positive linkage disequilibrium with HLA-DR7 and possibly HLA-A23, -A26, and -A29. These data suggest the existence of two genetically and functionally different subgroups of Bw44 antigens.
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PMID:Two subgroups of HLA Bw44 defined by cell-mediated lympholysis that differ in Bw44 expression on platelets and in patterns of genetic linkage disequilibrium. 618 11

Leukemia cells from a patient with chronic myelogenous leukemia (CML) in accelerated phase were used to generate CD4+, CD8- T lymphocyte lines from an unrelated normal subject sharing HLA-A2 and DR4 with the patient. In chromium release cytotoxicity assays, lines showed specificity for patient cells and were unreactive against third-party CML and K562 cells. Cytotoxicity was blocked by anti HLA-DR on target cells. Some lines showed preferential cytotoxicity to PHA-induced lymphoblasts and some to CML cells. There was a broad correlation between cytotoxicity to CML cells by 51Cr release and CFU-CM inhibition. However, even weakly cytotoxic lines were inhibitory to CML CFU-GM. This effect was partly mediated by the T cell line supernatant: four of five supernatants tested inhibited the growth of CFU-GM. Antibody neutralization studies demonstrated the presence of gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) in these supernatants. There was a greater suppression of CML CFU-GM when compared with CFU-GM from normal individuals. One supernatant from a noncytotoxic T cell line stimulated CFU-GM and was demonstrated by antibody neutralization studies to contain interleukin-3 (IL-3) and GM-CSF. These data indicate that alloreacting CD4 cells exert both cytotoxic and cytokine-mediated antileukemia effects which may relate to the graft-vs.-leukemia (GVL) effect in CML following bone marrow transplantation.
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PMID:Cellular and cytokine-mediated effects of CD4-positive lymphocyte lines generated in vitro against chronic myelogenous leukemia. 755 22

Chronic myelogenous leukemia (CML) is characterized by the t(9;22) translocation that results in chimeric genes encoding bcr/abl fusion proteins. Junction-spanning sequences represent unique tumor-specific moieties that might be exploited therapeutically. We investigate here the binding of synthetic bcr/abl peptides to various HLA-DR alleles and their recognition by T cells from normal donors and CML patients. A 23-mer b3/a2 peptide bound very strongly to isolated HLA-DRB1*1101 (Dw5) and relatively strongly to DRB1*0301 (Dw3) and DRB1*0402 (Dw10) molecules, as estimated using a competition assay. It failed to bind to several other DR alleles, including three different DR4 alleles. In contrast, a 23-mer b2/a2 peptide bound only to the DRB1*0301 (Dw3) allele. Peripheral blood mononuclear cells from normal donors were sensitized in vitro against the b3/a2 peptide. After four repetitive stimulations, T cells responding to the peptide were found at low frequency in 5 of the 11 donors tested. Three of the five were HLA-DR11+, and all three of the DR11+ donors tested were found to respond. T cells recognizing bcr/abl peptides were not identified in any of the CML patients studied, regardless of HLA type. Finally, even peptide-reactive T-cell lines from normal donors were not stimulated by native CML cells in the absence of exogenous peptide. These results show the presence of low-frequency major histocompatability complex class II-restricted bcr/abl-responses in the normal T-cell repertoire of donors with certain HLA types, but suggest that unmodified tumor cells cannot be recognized by such peptide-sensitized T cells.
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PMID:BCR/ABL leukemia oncogene fusion peptides selectively bind to certain HLA-DR alleles and can be recognized by T cells found at low frequency in the repertoire of normal donors. 882 31

In chronic myeloid leukemia (CML) the classical 9;22 translocation results in a BCR-ABL fusion gene, which encodes chimeric BCR-ABL fusion 210 kD oncoproteins (p210BCR-ABL). The two main p210BCR-ABL fusion variants in CML, b2a2 and b3a2 are examples of well characterized antigens expressed by malignant cells. The possibility of an immunotherapeutic approach involving the fusion part of p210BCR-ABL in CML has previously been illustrated by observed peptide binding to major histocompatibility complex (MHC) class I alleles and by demonstrating the immunogenicity of p210BCR-ABL breakpoint peptides. In this report we show that in vitro immunization of human T cells with a 17 amino acid (aa) peptide representing the p210BCR-ABL fusion region resulted in peptide specific CD4+ T-cell lines designated P4, P6, and P7. HLA DR4 (DRB1*0401) restricted T-cell line P4 and several subsequently derived clones recognized HLA-DRB1*0401 and p210b3a2-mRNA expressing blasts from an allogeneic patient with CML in blast crisis. Recognition appeared DR expression-dependent. No responses were observed with DR4 positive p210BCR-ABL negative cells or with p210b3a2 leukemic cells with absent or insufficient expression of DR4. These observations indicate that oncoprotein p210b3a2 can be degraded and processed for presentation by MHC class II molecules at the surface of leukemic cells. The BCR-ABL fusion region is in all likelihood presented as peptides by HLA DR and thus capable to act as a distinctive tumor antigen to peptide specific CD4+ T cells.
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PMID:Recognition of BCR-ABL positive leukemic blasts by human CD4+ T cells elicited by primary in vitro immunization with a BCR-ABL breakpoint peptide. 889 19

Peptides corresponding to the fusion site in 210 kD BCR-ABL protein b3a2 (p210b3a2) were previously shown to bind to several HLA class I and II alleles. We have found that b3a2 peptide-specific CD4-positive T-helper cells were able to recognize p210b3a2-positive chronic myelogenous leukemia (CML) blasts in a DR4 restricted manner. Until now, there were no reports of b2a2 breakpoint-specific human T-cell responses. Here we show that repetitive stimulation of T lymphocytes with a 17mer peptide covering the fusion region in p210b2a2 also leads to specific T-cell responses. CD4 and CD4/CD8 double-positive clones obtained from a b2a2 peptide-specific cell line were cytotoxic and proliferative in an HLA-DR2a (DRB5*0101) restricted fashion. Autologous Epstein-Barr virus (EBV) transformed cells, expressing BCR-ABL(b2a2) on transfection, and allogeneic HLA-DR matched p210b2a2-positive cells from CML patients were, however, not lysed. BCR-ABL peptide-specific T-cell clones did respond to autologous EBV cells transfected with invariant chain (li) cDNA in which the HLA class II-associated invariant chain peptide (CLIP) was replaced by a BCR-ABL b2a2 fusion oligonucleotide sequence, illustrating the potential of these T cells to recognize an endogenous BCR-ABL(b2a2) ligand.
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PMID:A BCR-ABL oncoprotein p210b2a2 fusion region sequence is recognized by HLA-DR2a restricted cytotoxic T lymphocytes and presented by HLA-DR matched cells transfected with an Ii(b2a2) construct. 1041 96

CML is characterized by the chromosomal translocation t(9;22) (q34;q11) resulting in the chimeric bcr-abl oncogene that encodes P210 fusion proteins with novel amino acid sequences in the breakpoint region. If these peptides derived from P210 are presented by HLA molecules on the cell membrane of leukemic cells an immunological response may occur. Recent studies using synthetic peptides identical to the bcr-abl fusion region revealed that some peptides are capable of binding to the class I molecules HLA-A2,-A3,-A11 and -B8 and the class II molecules HLA-DR1, -DR2, -DR3, -DR4 and -DR11. Moreover T cell responses have been induced against bcr-abl-derived synthetic peptides bound to some of these HLA molecules. For HLA class I, we have previously shown that individuals expressing HLA-A3 and -B8 have a diminished risk of development of CML. To assess a similar protective effect of class II molecules we performed a large multi-center study. This study compared the frequencies of HLA-DR1, -DR2, -DR3, -DR4 and -DR11 of patients with CML from the database of the EBMT (n = 1462) with unaffected individuals from the registry of Bone Marrow Donors Worldwide (n = 500 596). Patients and controls were matched per country. This analysis yielded significantly lower odds ratios (ORs) of 0.86 (95% CI 0.75-0.98) for HLA-DR3 and of 0.80 (95% CI 0.71-0.89) for HLA-DR4. The OR was 0.91 (95% CI 0.80-1.04) for HLA-DR1, 1.05 (95% CI 0.94-1.18) for HLA-DR2 and 0.87 (95% CI 0.74-1.01) for HLA-DR11. To assess a possible effect of the linkage disequilibrium between HLA-B8 and HLA-DR3 we found that coexpression of HLA-B8 and HLA-DR3 gave an OR of 0.84 (95% CI 0.72-0.98), whereas HLA-DR3 positive/HLA-B8 negative individuals showed an OR of 1.02 (95% CI 0.84-1.24). This means that the protective effect of HLA-DR3 of the development of CML was probably caused by its linkage disequilibrium with HLA-B8. In contrast, as there is no linkage disequilibrium of HLA-DR4 with HLA-A3 or HLA-B8, the results indicate that HLA-DR4 expression itself is associated with a diminished incidence of CML possibly by the presentation of bcr-abl breakpoint peptides in these HLA molecules on the membrane of the leukemic cells.
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PMID:HLA-DR4 is associated with a diminished risk of the development of chronic myeloid leukemia (CML). Chronic Leukemia Working Party of the European Blood and Marrow Transplant Registry. 1124 94

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL) have been implicated in antitumor immunity and therapy. In the present study, we investigated the sensitivity of Philadelphia chromosome (Ph1)-positive leukemia cell lines to TRAIL- or FasL-induced cell death to explore the possible contribution of these molecules to immunotherapy against Ph1-positive leukemias. TRAIL, but not FasL, effectively induced apoptotic cell death in most of 5 chronic myelogenous leukemia-derived and 7 acute leukemia-derived Ph1-positive cell lines. The sensitivity to TRAIL was correlated with cell-surface expression of death-inducing receptors DR4 and/or DR5. The TRAIL-induced cell death was caspase-dependent and enhanced by nuclear factor kappa B inhibitors. Moreover, primary leukemia cells from Ph1-positive acute lymphoblastic leukemia patients were also sensitive to TRAIL, but not to FasL, depending on DR4/DR5 expression. Fas-associated death domain protein (FADD) and caspase-8, components of death-inducing signaling complex (DISC), as well as FLIP (FLICE [Fas-associating protein with death domain-like interleukin-1-converting enzyme]/caspase-8 inhibitory protein), a negative regulator of caspase-8, were expressed ubiquitously in Ph1-positive leukemia cell lines irrespective of their differential sensitivities to TRAIL and FasL. Notably, TRAIL could induce cell death in the Ph1-positive leukemia cell lines that were refractory to a BCR-ABL-specific tyrosine kinase inhibitor imatinib mesylate (STI571; Novartis Pharma, Basel, Switzerland). These results suggested the potential utility of recombinant TRAIL as a novel therapeutic agent and the possible contribution of endogenously expressed TRAIL to immunotherapy against Ph1-positive leukemias.
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PMID:TNF-related apoptosis-inducing ligand (TRAIL) frequently induces apoptosis in Philadelphia chromosome-positive leukemia cells. 1250 34

Bcr-Abl-expressing primary or cultured leukemia cells display high levels of the antiapoptotic heat shock protein (hsp) 70 and are resistant to cytarabine (Ara-C), etoposide, or Apo-2L/TRAIL (TNF-related apoptosis-inducing ligand)-induced apoptosis. Conversely, a stable expression of the cDNA of hsp70 in the reverse orientation attenuated not only hsp70 but also signal transducers and activators of transcription 5 (STAT5) and Bcl-x(L) levels. This increased apoptosis induced by cytarabine, etoposide, or Apo-2L/TRAIL. Ectopic expression of hsp70 in HL-60 cells (HL-60/hsp70) inhibited Ara-C and etoposide-induced Bax conformation change and translocation to the mitochondria; attenuated the accumulation of cytochrome c, Smac, and Omi/HtrA2 in the cytosol; and inhibited the processing and activity of caspase-9 and caspase-3. Hsp70 was bound to death receptors 4 and 5 (DR4 and DR5) and inhibited Apo-2L/TRAIL-induced assembly and activity of the death-inducing signaling complex (DISC). HL-60/hsp70 cells exhibited increased levels and DNA binding activity of STAT5, which was associated with high levels of Pim-2 and Bcl-x(L) and resistance to apoptosis. Expression of the dominant negative (DN) STAT5 resensitized HL-60/hsp70 cells to cytarabine, etoposide, and Apo-2L/TRAIL-induced apoptosis. Collectively, these findings suggest that hsp70 inhibits apoptosis upstream and downstream of the mitochondria and is a promising therapeutic target for reversing drug-resistance in chronic myeloid leukemia-blast crisis and acute myeloid leukemia cells.
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PMID:Mechanistic role of heat shock protein 70 in Bcr-Abl-mediated resistance to apoptosis in human acute leukemia cells. 1538 81

In chronic myeloid leukemia (CML), experimental studies using synthetic peptides identical to the bcr-abl fusion region have revealed the capability of specific peptides to bind to human leukocyte antigen (HLA) class I molecules (HLA-A2, A3, A11, B8) and class II molecules (HLA-DR1, DR2, DR3, DR4 and DR11). Individuals expressing HLA-A3, B8 or DR4 have a diminished risk for the development of CML in Caucasian populations. A statistically significant increase in the frequency of Cw3 and Cw4 antigens in Caucasians and European CML patients has been reported. However, HLA associations in CML have not been reported in India. In lieu of the allelic diversity of HLA in the Indian population, the present study assessed the possibility of an association of HLA molecules in Indian patients with CML. HLA A, B, C and DRB1 antigen associations in 180 clinically diagnosed Indian CML patients (aged 17 - 54 years) were analysed and compared with age-matched (n = 100) healthy individuals from the same ethnic background. In the HLA class I antigen distribution, a significant decrease was observed in HLA-A11 (25.6% versus 39%; P = 0.027, odds ratio (OR) = 0.54, 95% confidence interval (CI) = 0.31 - 0.94) and HLA-Cw6 (7.8% versus 20%; P = 0.005, OR = 0.34, 95% CI = 0.15 - 0.74). Among the DRB1 alleles, HLA-DRB1*13 (7.8% versus 17%; P = 0.031, OR = 0.41, 95% CI = 0.18 - 0.93) was decreased in CML patients. However, the differences for HLA-A11 (P(c) = 0.351) and DRB1*13 (P(c) = 0.403) did not remain significant after the application of a correction factor for the P-value. These results suggest that the development of CML is apparently associated with HLA phenotypes specific to each population and indicate that expression of HLA-Cw6 may result in a protective effect on CML acquisition in the Indian population.
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PMID:Human leukocyte antigens in Indian patients with chronic myeloid leukemia. 1632 60

Primitive quiescent CD34(+) chronic myeloid leukemia (CML) cells are more biologically resistant to tyrosine kinase inhibitors than their cycling counterparts; however, graft-versus-leukemia (GVL) effects after allogeneic stem cell transplantation (SCT) probably eliminate even these quiescent cells in long-term surviving CML transplant recipients. We studied the progeny of CD34(+) cells from CML patients before SCT, which were cultured 4 days in serum-free media with hematopoietic growth factors. BCR-ABL expression was similar in both cycling and quiescent noncycling CD34(+) populations. Quiescent CD34(+) cells from CML patients were less susceptible than their cycling CD34(+) and CD34(-) counterparts to lysis by natural killer (NK) cells from their HLA-identical sibling donors. Compared with cycling populations, quiescent CD34(+) CML cells had higher surface expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors DR4 and DR5. Bortezomib up-regulated TRAIL receptor expression on quiescent CD34(+) CML cells, and further enhanced their susceptibility to cytotoxicity by in vitro expanded donor NK cells. These results suggest that donor-derived NK cell-mediated GVL effects may be improved by sensitizing residual quiescent CML cells to NK-cell cytotoxicity after SCT. Such treatment, as an adjunct to donor lymphocyte infusions and pharmacologic therapy, may reduce the risk of relapse in CML patients who require treatment by SCT.
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PMID:Primitive quiescent CD34+ cells in chronic myeloid leukemia are targeted by in vitro expanded natural killer cells, which are functionally enhanced by bortezomib. 1892 53


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