Chromosomal Rearrangements Affecting ABL1 in T-Cell Acute Lymphoblastic Leukemia.

Abstract

T-cell Acute Lymphoblastic Leukemia (T-ALL) is a heterogeneous entity with several biologically distinct subtypes that differ in clinical outcome. Cytogenetics in T-ALL shows recurrent involvement of TCR a/d (14q11) and TCR b (7q34) rearrangements. The Philadelphia translocation, encoding the BCR-ABL1 (BCR-ABL) fusion gene, is typically found in chronic myeloid leukemia (CML) and precursor B-cell acute lymphoblastic leukemia (B-ALL), but is exceptionally rare in T-ALL. To study the potential involvement of ABL1 gene rearrangements in T-cell malignancies, we screened 90 T-ALL cases by fluorescence in situ hybridization (FISH), using BCR and ABL1 probes. No BCR-ABL1 rearrangements were detected, but 5 patients showed amplification of ABL1 and are described in a separate abstract and 2 patients showed a chromosomal rearrangement affecting ABL1. The first patient (male, age 16, 455x109 WBC/L, 99% blasts, cortical T immunophenotype) showed a cryptic t(9;14)(q34;q32). This was demonstrated in 7/12 metaphases and 60% of nuclei using FISH with the 5′/3′-ABL1 probes RACE-PCR detected a fusion between EML1 at 14q32 and ABL1 at 9q34. The fusion transcript joins exon 1–18 of EML1 to exon 2 of ABL1 and generates an ORF of 4926 nt. The functional characterization of the fusion protein is ongoing. The second patient (male, age 16, 25x109 WBC/L, 35% blasts, mature T-cell immunophenotype) showed a 47, XY, +10[5], idem, inv(9)(p21q34)[2}]/46, XY[9] karyotype. One third of the metaphases are tetraploid with the same distribution of abnormalities. The split signals obtained with the 5′-/3′ABL1 probes in the inv(9) subclone point to an ABL1 rearrangement that is being characterized at the present. These result suggest that ABL1 rearrangements are a rare but recurrent event in T-cell malignancies and support a role of ABL1 in T-cell biology. The therapeutic potential of ABL1 inhibitors for treating this group of T-ALL needs to be explored.