A Patient with Philadelphia-Negative Acute Lymphoblastic Leukemia with a FISH-Negative Cryptic BCR-ABL1 Rearrangement Detected by PCR and Sequencing Analysis

Abstract

The BCR-ABL1 rearrangement found in hematologic malignancies such as chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL). About 5-10% of patients with CML and ALL lack cytogenetic evidence of the Ph chromosome detected only by fluorescence in situ hybridization (FISH) and/or reverse transcription-polymerase chain reaction (RT-PCR) without any cytogenetic evidence of Ph chromosome. Here we describe a patient with Ph-negative ALL and a FISH-negative cryptic BCR-ABL1 rearrangement, as confirmed by RT- PCR and sequencing analyses. A 20-year-old female with Down syndrome and relapsed ALL was referred to our hospital. All 20 metaphase cells analyzed had a karyotype by conventional methods of 47, XX, +21 and FISH analysis yielded a signal for BCR-ABL1 consistent with a normal pattern. However, multiplex RT-PCR revealed an atypical band indicating the possibility of BCR-ABL1 translocation, which was confirmed by Split-out PCR, real-time PCR and direct sequencing. We revealed that this patient has a dual transcription of typical b3a2 and atypical b2a2 resulted from partial duplication of BCR exon 13, combined with ABL1 exon 2. Although cryptic BCR-ABL1 rearrangements are rare, they affect treatment regimens, making them clinically important. Precise molecular work up along with standard diagnostic tools used to detect BCR-ABL1 rearrangements are recommended for these patients.