BCR-ABL Is Not an Immunodominant Antigen in Chronic Myelogenous Leukemia

Grünebach, Frank; Mirakaj, Valbona; Mirakaj, Valdete; Müller, Martin; Brümmendorf, Tim H.; Brossart, Peter

doi:10.1158/0008-5472.can-05-2868

Cited by 28 publications

(14 citation statements)

References 46 publications

(38 reference statements)

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“…In contrast, they were able to lyse autologous DC electroporated with RNA from patients with acute myeloid leukemia (AML), indicating that some antigens shared by these malignant cells are involved and recognized by these CTL. 7 Therefore, BCR-ABL is processed and presented by Ph'-positive cells but is not the immunodominant antigen that induces CD8 + T lymphocytes in competition with other tumor-associated antigens. However, the nature of these possible antigens is unknown.…”

Section: 3mentioning

confidence: 99%

Epigenetic regulation of human cancer/testis antigen gene, HAGE, in chronic myeloid leukemia

Román‐Gómez

Jiménez-Velasco²,

Agirre³

et al. 2007

Haematologica

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Background and ObjectivesCancer testis antigens (CTA) provide attractive targets for cancer-specific immunotherapy. Although CTA genes are expressed in some normal tissues, such as the testis, this immunologically protected site lacks MHC I expression and as such, does not present self antigens to T cells. To date, CTA genes have been shown to be expressed in a range of solid tumors via demethylation of their promoter CpG islands, but rarely in chronic myeloid leukemia (CML) or other hematologic malignancies. Design and MethodsIn this study, the methylation status of the HAGE CTA gene promoter was analyzed by quantitative methylation-specific polymerase chain reaction (MSP) and sequencing in four Philadelphia-positive cell lines (TCC-S, K562, KU812 and KYO-1) and in CML samples taken from patients in chronic phase (CP n=215) or blast crisis (BC n=47). HAGE expression was assessed by quantitative reverse transcriptase-polymerase chain reaction. ResultsThe TCC-S cell line showed demethylation of HAGE that was associated with overexpression of this gene. HAGE hypomethylation was significantly more frequent in BC (46%) than in CP (22%) (p=0.01) and was correlated with high expression levels of HAGE transcripts (p<0.0001). Of note, in CP-CML, extensive HAGE hypomethylation was associated with poorer prognosis in terms of cytogenetic response to interferon (p=0.01) or imatinib (p=0.01), molecular response to imatinib (p=0.003) and progression-free survival (p=0.05). Interpretations and ConclusionThe methylation status of the HAGE promoter directly correlates with its expression in both CML cell lines and patients and is associated with advanced disease and poor outcome. (p210), which has abnormal tyrosine-kinase activity that is central to the pathogenesis of the disease.1 Treatment of CML has been notably improved by imatinib mesylate, a potent tyrosinekinase inhibitor that blocks the kinase activity of p210, thus inhibiting proliferation of Ph'-positive progenitors. 2In the past 5 years, the results of imatinib treatment of CML have established this drug as the first-line therapy for CML patients.3 However, both the persistence of molecular disease in most imatinib-treated patients, as well as the observation that discontinuation of the drug usually results in a rapid loss of the response, indicate that it is unlikely that imatinib alone can cure CML. 2,3An alternative attempt to target CML cells is an active, specific immunotherapy (e.g. a vaccine). In fact, because of the unique amino acid sequence of p210 at the fusion point, the protein is a tumor-specific antigen to which an immune response can be induced. In some studies it has been shown that peptides derived from the p210 fusion point (b3a2) can bind to several HLA class I and class II molecules and thus generate peptidespecific dendritic cells (DC) and cytotoxic T lymphocyte (CTL) responses in vitro. 4,5 Preliminary clinical data suggest that the addition of a b3a2-specific vaccine to b3a2-CML patients treated with conventional treatment might favor a furt...

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Section: 3mentioning

confidence: 99%

Epigenetic regulation of human cancer/testis antigen gene, HAGE, in chronic myeloid leukemia

Román‐Gómez

Jiménez-Velasco²,

Agirre³

et al. 2007

Haematologica

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“…Other approaches tried to exploit the presence of proteins overexpressed by CML cells, such as proteinase-3 and prame (19,20).…”

Section: Introductionmentioning

confidence: 99%

Alternative BCR/ABL Splice Variants in Philadelphia Chromosome–Positive Leukemias Result in Novel Tumor-Specific Fusion Proteins that May Represent Potential Targets for Immunotherapy Approaches

Volpe¹,

Cignetti²,

Panuzzo³

et al. 2007

Cancer Research

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Imatinib currently represents the standard treatment in the early chronic phase of chronic myelogenous leukemia (CML), thanks to the high percentage of cytogenetic complete remission achieved, but it is yet unclear to what extent it can eradicate leukemia. Therefore, different vaccination strategies have been suggested, mainly based on the exploitment of the junctional peptides spanning the fusion region of the Bcr/Abl proteins. To identify new potential immunologic targets, 63 Philadelphia chromosome-positive patients and 6 BCR/ABL-positive cell lines were tested in nested reverse transcriptase PCR to detect the presence of BCR/ABL transcripts arising from the alternative splicing of the main BCR/ ABL transcripts. We could detect BCR/ABL transcripts with junctions between BCR exon 1, 13, or 14 and ABL exon 4 in f80% of patients and 84% of cell lines, beside the main fusion transcripts. Translation products of these transcripts were characterized at their COOH terminus by a large amino acid portion derived from the out of frame (OOF) reading of ABL gene. These proteins were detected in BCR/ABL-positive cell lines by immunoprecipitation and immunohistochemistry. Finally, we determined whether OOF-specific CD8 + T cells could be found in the peripheral blood of CML patients and whether they could acquire effector function following in vitro sensitization with OOF-derived peptides predicted to bind to human leucocyte antigen (HLA)-A2 and HLA-A3 molecules. We detected the presence of OOF-specific CD8 +

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“…In approximately 75% of cases the investigators failed to elicit in vitro sizable CTL responses to Bcr-Abl epitopes in healthy donors as well as in patients with CML and found that Bcr-Abl protein is apparently not an immunodominant antigen in CML (32,33). Study of Abu-Eisha et al (34) showed that most normal subjects and CML patients developed no proliferative responses to the 23-mer b3a2 fusion peptide.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, hypothesis appeared that not Bcr-Abl itself but genes that are up-regulated by the Bcr-Abl kinase activity may represent the crucial antigens for the induction of a cytotoxic T-cell response against CML cells (33,38). Scheich et al (38) demonstrated that the constitutively active kinase domain of Bcr-Abl has a key role in enhancing the immunogenicity of Bcr-Abl cells as the HLA class I-restricted T-cell responses were dominated by Bcr-Abl-regulated antigens, and not by Bcr-Abl itself.…”

Section: Discussionmentioning

confidence: 99%

Bcr-Abl fusion sequences do not induce immune responses in mice when administered in mouse polyomavirus based virus-like particles

Hrušková

Morávková²,

Babiarova³

et al. 2009

Int J Oncol

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Abstract. Mouse polyomavirus-like particles (MPyV-VLPs) carrying inside a fragment of the Bcr-Abl hybrid protein containing the epitope of chronic myeloid leukemia fusion region were prepared. A sequence encoding 171 amino acids covering Bcr-Abl breakpoint was fused to the C-terminal part of VP3 minor protein connecting it to the VP1 capsomeres. Chimeric particles, the Bcr-Abl VLPs, were tested for their ability to induce Bcr-Abl specific immune response in mice after their intranasal (i.n.) or intraperitoneal (i.p.) administration without any other adjuvants. Bcr-Abl VLPs induced strong anti-VP1 immune response in both i.n. and i.p. immunized mice. As expected, neither IgG nor IgM anti-Bcr-Abl specific antibodies were detected in the sera of immunized animals. Surprisingly, no specific CTL (cytotoxic T-lymphocyte) activity was proved using two different methods (in vitro cytotoxicity assay with CFSE-labeled target cells and highly sensitive cytotoxicity assay using MHC class I Bcr-Abl specific pentamers). In addition, no proliferative response of T-cells of i.n. immunized mice after in vitro restimulation with antigen-pulsed bone marrow-derived dendritic cells was observed. Taken together, Bcr-Abl breakpoint epitopes appeared to be weak immunogens and even MPyV-VLPs did not provide sufficient adjuvant ability to support induction of immune responses specific to Bcr-Abl fusion zone epitope.

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BCR-ABL Is Not an Immunodominant Antigen in Chronic Myelogenous Leukemia

Cited by 28 publications

References 46 publications

Epigenetic regulation of human cancer/testis antigen gene, HAGE, in chronic myeloid leukemia

Epigenetic regulation of human cancer/testis antigen gene, HAGE, in chronic myeloid leukemia

Alternative BCR/ABL Splice Variants in Philadelphia Chromosome–Positive Leukemias Result in Novel Tumor-Specific Fusion Proteins that May Represent Potential Targets for Immunotherapy Approaches

Bcr-Abl fusion sequences do not induce immune responses in mice when administered in mouse polyomavirus based virus-like particles

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