Leukemia-associated fusion proteins, dek-can and bcr-abl, represent immunogenic HLA-DR-restricted epitopes recognized by fusion peptide-specific CD4+ T lymphocytes

Abstract

Although CD4 + helper T lymphocytes have been demonstrated to play an important role in antitumor immune response, only a few epitopes of tumor-associated antigens recognized by HLA class II-restricted CD4 + T lymphocytes have been identified. In the present study, we addressed the question of whether leukemia-associated fusion proteins are recognized by CD4 + T lymphocytes. Immature dendritic cells (DCs) were loaded with necrotic or apoptotic leukemia cells with t(6;9) or t(9;22) and then cocultured with the dek-can fusion peptide-specific or the bcrabl fusion peptide-specific CD4 + T lymphocyte clone. The dekcan peptide-specific and bcr-abl peptide-specific CD4 + T lymphocyte clones produced interferon-␥ (IFN-␥) when they were cocultured with HLA-DR-matched but not with mismatched DCs which had been loaded with apoptotic as well as necrotic leukemia cells with t(6;9) and t(9;22), respectively. IFN-␥ production by CD4 + T lymphocyte clones in response to stimulation with DCs loaded with leukemia cells was inhibited by the anti-HLA-DR monoclonal antibody. These data indicate that the acute myelogenous leukemia-associated fusion protein, dek-can, and chronic myelogenous leukemia-associated fusion protein, bcrabl, are both processed and presented by DCs to the fusion peptide-specific CD4 + T lymphocytes.

DEK-CAN molecular monitoring of myeloid malignancies could aid therapeutic stratification

“…This suggests both that it may not be necessary to achieve RQ-PCR negativity before allograft, and also a potential GVL effect against the leukemic clone in this disease, in keeping with in-vitro data. 35,36 Allogeneic HSCT has a positive impact on OS in AMLs with unfavorable cytogenetics, including t(6;9). 31 Based on a review of the literature, only a few other DEK-CAN þ patients obtained a DFS longer than 2 years, of which three had undergone allogeneic HSCT.…”

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

“…Although more than 200 chromosomal translocations have been identified in AML, only a select minority are known to give rise to antigenic proteins. Among these are the fusion proteins AML1-ETO, 5 DEK-CAN 6 and promyelocytic leukemia-retinoic acid receptor a (PML-RARa), 7,8 resulting from the t(8;21), t(6;9) and t(15;17) chromosomal translocations, respectively. 9 In addition, gene mutations occurring in tumor cells may result in the formation of mutant tumor-specific proteins.…”

Serum from mice immunized in the context of Treg inhibition identifies DEK as a neuroblastoma tumor antigen

“…This is fascinating, as the breaking of tolerance to a self/tumor-associated antigen, as demonstrated by an IFN-γ mediated immune response, is a key characteristic of generating Th1 immunity. Further evidence for the ability to generate an immune response specific for DEK was seen when a human CD4 T cell clone specific to the DEK-CAN fusion protein produced IFN-γ upon co-culture with dendritic cells loaded with either apoptotic or necrotic t(6;9) leukemia cells [38]. Another potential mechanism for the induction of an immune response to self-proteins is the production of a truncated transcript by the tumor itself.…”