Acute promyelocytic leukemia with a cryptic insertion of RARA into TBL1XR1

Acute promyelocytic leukemia (APL) is cytogenetically characterized by the t(15;17) (q24;q21), although cases without this translocation exist. These cases are referred to as "cryptic" or "masked" translocations. Additionally, fewer than 5% of APL cases have another partner gene fused to the RARA gene. The TBL1XR1-RARA fusion gene has recently been reported as a novel RARA-associated fusion gene. We report a case with TBL1XR1-RARA and a masked translocation that was not detected by conventional tests for RARA-associated translocations. Three-year-old girl was diagnosed with APL based morphological findings, although conventional tests for RARA-associated chimeric genes were negative. She received all-trans retinoic acid treatment, but that was not effective. She achieved a complete remission (CR) by conventional multidrug chemotherapy, but had extramedullary relapse 2 years after onset. She underwent cord blood transplantation (CBT) in her second CR and is currently alive. To investigate the underlying pathogenesis of this unique case, we performed whole-genome sequencing and found a cryptic insertion of RARA gene into the TBL1XR1 gene. The transcript of the chimeric gene, TBL1XR1-RARA, was confirmed as an in-frame fusion by RT-PCR. In conclusion, we found using next-generation sequencing (NGS) a TBL1XR1-RARA fusion in a child with variant APL without the classic karyotype. Cryptic insertion could also occur in cases other than APL with PML-RARA. Variant APL has many variants and NGS analysis should therefore be considered for APL variant cases, even for those without RARA translocation detected by conventional analysis.