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In-frame fusion of two transcription factor genes, TEL (ETV6) on chromosome 12p and AML1 (RUNX1) on chromosome 21q, is thought to be an initiating event in ∼25% of childhood acute lymphoblastic leukemias (ALL). TEL-AML1 fusion leads to the expression of a chimeric oncoprotein which interferes with the function of the normal AML1 protein, leading to arrested B cell development, and enhanced B cell progenitor self-renewal. In vitro studies showed that a TEL-AML1 junctional peptide induced HLA-DP-restricted CD4+ T cell responses. Although expression of TEL-AML1 by pro-leukaemic cells makes it an attractive immunotherapeutic target, information on the number, position, and population distribution of HLA-DR-restricted CD4+ T cell epitopes in TEL-AML1 has not been published. Here, we used the artificial neural network algorithm, NetMHCIIpan (Nielsen et al, PLoS Computational Biology, 2008, 4(7), e1000107) to predict DR-restricted T cell epitopes in TEL-AML1. The 797 residue fusion oncoprotein was screened using NetMHCIIpan to identify 9-mer DR-binding core peptides. 15-mer peptide sequences were submitted in FASTA format to the NetMHCIIpan server (http://www.cbs.dtu.dk/services/NetMHCIIpan/) to facilitate discovery of peptides with strong binding affinity (IC50:<50 nM). Consensus T cell epitopes predicted to provide maximum coverage across common DR alleles in 4 ethnic groups were identified. Overlapping 15-mer junctional sequences were screened to identify a 9-mer DR-binding core sequence, and P1,4,6, and 9 substituted with all 20 amino acids to identify junctional sequences with enhanced (heteroclitic) binding affinity. NetMHCIIpan predicted 45 TEL-AML1 epitopes binding to 22 common DR alleles in 4 ethnic groups. Fourteen epitopes are in TEL and 31 in AML1, with 5 epitopes binding to 5-8 DR alleles, and 1 binding to 10 alleles. Three TEL peptides achieve the greatest population coverage across all ethnic groups, one peptide (266IQLMPSPIM274) giving maximal coverage (25.5-50.1%). Weak DRB1*0101-restricted binding of a junctional peptide (332IGRIA/ECIL340) (415 nM) was strongly increased (52 nM) by substituting serine for glutamic acid at the P6 position. A junctional peptide (332FGRMA/SCIV343) with substitutions at P1, P4 and P9 had enhanced DRB1*0101 affinity (13 nM). These predictions suggest wide population coverage of a small number of strongly binding TEL-AML1 epitopes. The binding affinity of a junctional peptide is enhanced by substituting key anchor residues. Functional studies are now required to distinguish CD4+ T cell-activating TEL-AML1 epitopes inducing anti-leukemic, autoimmune, and regulatory T cell responses. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2395.