LAUSR

Dear Editor, The identification of recurrent gene rearrangements in the clinical laboratory is important for a precise diagnosis and treatment decisions in patients with acute leukemia [1]. Currently, cytogenetic tests and reverse transcription-PCR (RT-PCR) are used for the detection of gene rearrangements. However, the genes involved in rearrangement and even an exact breakpoint can be detected by chromosomal microarray (CMA) [2]. Here, we report PAX5-ETV6 rearrangement identified by CMA in a patient with acute lymphoblastic leukemia (ALL). A 16-year-old boy presented with pancytopenia, with a white blood cell count of 0.9 × 10/L comprising 30% of blasts. His bone marrow was packed with leukemic blasts and flow cytometric analysis indicated B-cell ALL (BALL). Conventional karyotyping demonstrated 45,XY,12,dic(9;12)(p13;p13) in 8 out of 10 metaphases. Fluorescence in situ hybridization (FISH) test using CDKN2A/CEP9 probe (Abbot Molecular, Des Plains, IL, USA) showed deletion of the CDKN2A gene at 9p21. The result of RT-PCR using the HemaVision kit (DNA Diagnostic, Aarhus, Denmark) was negative. For the unbalanced translocation, CMA with CytoScan 750 K array (Affymetrix, Santa Clara, CA, USA) was performed to identify the exact location and extent of the deletions, and the result included arr[hg19] 9p24.3p13.2(208,45437,004,901)x1, 12p13.33p13.2(173,786-11,933,797)x1, 12p13.2p11.23(12,691,302-27,483,306)x1, indicating a 37 Mbp deletion on chromosome 9 and discontinuous 12 Mbp and 14 Mbp deletions on chromosome 12 (Fig. 1). Among genes located in these regions, we put weight on ETV6 because the direction of transcription is in line with the partner gene, PAX5, after translocation. According to the CMA result, 3′ of exon 4 of PAX5 was fused with 5′ of exon 3 of ETV6 (Fig. 1). RT-PCR for PAX5-ETV6 fusion transcript and an additional FISH test using ETV6 breakapart probe confirmed the gene fusion with the exact breakpoint (Fig. 1). PAX5 rearrangement is observed in 2.5% of B-ALL and a number of partner genes of PAX5 have been identified so far [3]. Interestingly, abnormalities in the PAX5 gene are frequently associated with dicentric chromosomes, especially dic(9;12), although the locations of the breakpoint show a wide variety [3–6]. The PAX5-ETV6 fusion was found in 18 out of 19 (95%) patients bearing dic(9;12) in a previous study [3]. Dicentric(9;12) is a recurrent translocation in B-ALL [4, 5] and more frequently associated with PAX5-ETV6 fusion; however, it is reported to coexist with other chromosomal changes such as t(12;21), i.e., ETV6-RUNX1 fusion, suggesting that they are important cooperating events [2, 6]. The location of the breakpoint of ETV6 gene is different in each case, intron 2 in PAX5-ETV6 and intron 4 in ETV6-RUNX1 [7]. PAX5 is essential for B-lineage commitment and maintenance and the PAX5-ETV6 fusion protein is known to be a stronger competitive inhibitor of wild-type PAX5 [1, 3]. The PAX5-ETV6 oncoprotein contributes to leukemogenesis involving pre-B-cell receptor signaling which leads to the proliferation, survival, and tissue infiltration of leukemic B cells [8]. Bone marrow transplantation is not recommended as the dic(9;12) in ALL is associated with an excellent prognosis [5, 9]. * Borahm Kim [email protected]