The t(10;14)(q24;q11) chromosomal translocation found in malignant cells of 5-10% of patients with T-cell acute lymphoblastic leukemia (T-ALL) involves the T-cell receptor delta chain gene on chromosome 14 and a breakpoint cluster region on chromosome 10. The candidate proto-oncogene tcl-3, thought to be involved in the pathogenesis of t(10;14) T-ALL, was cloned and found to be elevated in expression in leukemic cells harboring the t(10;14) translocation. Sequence analysis revealed that tcl-3 is a new homeobox-containing gene. Comparison of the tcl-3 cDNA and its 5' genomic sequences with DNA sequences from the t(10;14) translocation breakpoints showed that this gene is structurally altered in four patients with t(10;14)(q24;q11) T-ALL. These findings suggest that homeobox-containing genes that normally act as transcription factors may contribute to T-cell leukemogenesis when abnormally expressed.