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Modified Array-based Comparative Genomic Hybridization Detects Cryptic and Variant PML-RARA Rearrangements in Acute Promyelocytic Leukemia Lacking Classic Translocations

Gruver, Aaron M. MD, PhD*; Rogers, Heesun J. MD, PhD*; Cook, James R. MD, PhD*; Ballif, Blake C. PhD; Schultz, Roger A. PhD; Batanian, Jacqueline R. PhD; Fesler, Mark J. MD§; Tubbs, Raymond R. DO*

Diagnostic Molecular Pathology: March 2013 - Volume 22 - Issue 1 - p 10–21
doi: 10.1097/PDM.0b013e31825b8326
Original Articles

Acute promyelocytic leukemia (APL) is typically defined at the molecular level by a reciprocal translocation of the promyelocytic leukemia (PML) and retinoic acid receptor α (RARA) genes. An accurate diagnosis of APL is critical for appropriate choice of therapy and prognostic assessment. Cryptic and variant rearrangements in APL are discoverable by a variety of molecular methods including fluorescence in situ hybridization (FISH), reverse transcriptase polymerase chain reaction, or gene sequencing. Rare reports of FISH-negative APL harboring cryptic rearrangements of PML-RARA detected by reverse transcriptase polymerase chain reaction or sequencing have been described. Here, we describe the detection of cryptic or variant PML-RARA rearrangements by translocation-based comparative genomic hybridization (tCGH), a recently described modification of traditional CGH technology that facilitates the detection of balanced translocations by means of the linear amplification of a potential translocation breakpoint region(s), in 2 unusual cases of APL. One tumor lacked detectable t(15;17) by karyotype and FISH, and the other tumor lacked the typical morphologic and immunophenotypic features of APL and had a variant 3-way translocation involving PML and RARA. PML-RARA translocations were identified by tCGH in both cases providing confirmation of the diagnosis of APL. These data emphasize the benefit of using complementary molecular methods including tCGH for detecting cryptic and variant PML-RARA translocations in unusual cases of APL.

*Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH

Signature Genomic Laboratories, PerkinElmer Inc., Spokane, WA

Pediatrics Department, SSM Cardinal Glennon Children Medical Center, Saint Louis University Medical Center

§Cancer Center, Saint Louis University, St Louis, MO

R.A.S. and B.C.B. are employees of Signature Genomic Laboratories, PerkinElmer Inc., Spokane, WA. The remaining authors declare no conflict of interest.

Reprints: Aaron M. Gruver, MD, PhD, Department of Clinical Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH 44195 (e-mail:

© 2013 Lippincott Williams & Wilkins, Inc.