Translocations between chromosomes 9 and 22 result in the generation of the novel fusion protein that is a critical oncogene in both chronic myelogenous leukemia (CML) and B cell acute lymphoblastic leukemia (B-ALL). The use of tyrosine kinase inhibitors (TKIs), such as imatinib that targets the BCR-ABL fusion protein, has proven to be extremely successful in patients with CML. In contrast, TKIs have not been very effective in treating patients with B-ALL, largely due to the acquisition of resistance mutations that render the inhibitors non-functional. Since the BCR-ABL fusion generates a foreign antigen that can be seen by the immune system, an alternative approach to treating BCR-ABL+ ALL involves immunotherapy. The potential efficacy of such an approach is suggested by a subset of BCR-ABL+ B-ALL patients with very low levels of minimal residual disease (MRD). Low MRD is associated with patients that have BCR-ABL-specific T cells that make interferon-gamma; loss of these T cells correlates with an increase in MRD and poor patient outcome. Likewise, in a mouse model of BCR-ABL+ B-ALL, we have observed that T cells exist that can mount robust immune responses to the BCR-ABL fusion peptide. A key question is why such T cells in both mice and humans typically do not eliminate BCR-ABL+ leukemic cells. This has been a difficult question to answer because previous studies have not been able to examine the endogenous T cell response to the BCR-ABL peptide. To address this issue this project will track the CD4+ T cell response to BCR-ABL-induced B-ALL using MHC Class II: peptide tetramers. These tetramers are composed of a 13 amino acid peptide that spans the e1a2 BCR-ABL breakpoint bound to I-Ab (BAp:I-Ab), which is the MHCII molecule in C57BL/6 mice. This novel reagent will allow us to determine the number of BAp:I-Ab-specific T cells in a naive mouse and establish how well these cells expand following strong immunization with the BAp peptide or following initiation of BCR- ABL+ leukemia. This approach will allow us to determine whether the failure of BAp:I-Ab specific T cells to eliminate BCR-ABL+ cells is due to a defect in antigen presentation, induction of anergy, deletion of BAp:I-Ab- specific cells or immune deviation (i.e., differentiatio into Treg, TFH or TH2 cell lineages). Based on these findings we will then pursue a variety of strategies to enhance BAp:I-Ab-specific immune responses. Our hypothesis is that generating CD4+ T cells with cytolytic activity will be critical for inducing effective T cell immunity to BCR ABL+ B-ALL. Finally, to enhance the translational potential of my findings we will generate BAp:DR4 tetramers that will allow us to track similar anti-leukemia responses in mice expressing human DR4 (B6.DR4 mice). The results of these studies could then be directly applied to human patients as the BAp:DR4 tetramer could be used to track BAp-specific T cell in patients with BCR-ABL that are DR4+ or that receive a DR4+ bone marrow transplant.
Patients with some forms of leukemia continue to have very poor outcomes. The studies in this grant will focus on a subset of B cell leukemia involving a chromosomal translocation called BCR-ABL for which there is currently no effective treatment. The studies in this grant application will study the initial immune response to this leukemia in an effort to optimize this response and provide new treatment options for BCR-ABL+ patients.
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