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 nave 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.
NIH ExPorter
NIH ExPorter