Identification of a variant RAR gene rearrangement in a patient with acute promyelocytic leukemia. B.M. Shearer¹, J.G. Keefe¹, C. Rubin de Celis², A. Vendrell², R.F. McClure¹, E.C. Thorland¹, R.P. Ketterling¹. 1) Dept. of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; 2) Brackenridge Hospital, Austin, TX.
   Acute promyelocytic leukemia (APL) comprises approximately 10% of all acute myelogenous leukemias (AML). The hallmark genetic aberration is a translocation between chromosomes 15 and 17 resulting in the gene fusion of PML (promyelocytic leukemia) at 15q22 and RAR (retinoic acid receptor alpha) at 17q21 in approximately 95% of cases. Infrequently, RAR gene fusion with variant gene partners has been observed in APL. Variant gene partners include PLZF at 11q23, NuMA at 11q13, NPM at 5q35, and Stat5b at 17q21.2. Treatment with all-trans retinoic acid (ATRA) induces a transient complete remission and when consolidated with conventional chemotherapy produces a cure in 70-90% of patients. Herein, we describe a 42 year old male presenting with AML whose bone marrow contained nearly 100% promyelocytes with secondary granules and Auer rods. Chromosome analysis revealed a 46,XY karyotype and both RT-PCR and D-FISH failed to demonstrate PML-RAR fusion. However, interphase FISH analysis demonstrated a small split of the RAR probe, which was found to co-localize on the abnormal chromosome 17 by metaphase FISH. Break-apart FISH for RAR revealed a deletion of the centromeric portion of the probe. In combination, these results suggest a cryptic rearrangement on chromosome 17q, which may represent an inversion/deletion mechanism resulting in aberrant expression of RAR with a new partner. A candidate gene of interest includes Stat5b for which a sole APL patient demonstrated Stat5B-RAR fusion due to an interstitial deletion of 17q. However, since subsequent ATRA treatment of our patient induced remission and the previously described Stat5b-RAR patient was refractory to ATRA, a novel gene may be the target of RAR upregulation in our patient. Additional studies to identify the partner gene have been initiated. Detailed genetic results for this patient, a review of the literature, and a discussion of the pathogenetic model for this variant RAR gene rearrangement will be presented.