Translocations between chromosomes 9 and 22 result in the generation of the novel BCR-ABL 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, I 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 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 my project will track the CD4+ T cell response to BCR-ABL-induced B-ALL using MHC Class II:peptide tetramers that I will develop. These tetramers will be 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 me to determine the number of BAp:I-Ab-specific T cells in a na?ve mouse and establish how well these cells expand following strong immunization with the BAp peptide or inoculation with BCR-ABL+ leukemia cells. This approach will allow me 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., differentiation into Treg, TFH or TH2 cell lineages). Based on these findings I will then pursue a variety of strategies to enhance BAp:I-Ab-specific immune responses. My hypothesis is that generating CD4+ T cells with cytolytic activity will be critical for inducing effective T cell immuity to BCR- ABL+ B-ALL. These studies will provide insights that should ultimately lead to improved immunotherapy for patients with BCR-ABL+ leukemia.

Public Health Relevance

Patients with some forms of leukemia continue to have very poor outcomes. I will focus on one form of B cell leukemia involving a chromosomal translocation called BCR-ABL for which there is currently no effective treatment. In this grant application I will attempt to optimize immune responses to this leukemia in an effort develop new treatment options for these patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F09B-P (20))
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Schmidt, Michael K
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University of Minnesota Twin Cities
Schools of Medicine
United States
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