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Do RARA/PML fusion gene deletions confer resistance to ATRA-based therapy in patients with acute promyelocytic leukemia?

Leukemia volume 20, pages 2193–2195 (2006)Cite this article

Acute promyelocytic leukemia (APL) is characterized by the translocation t(15;17)(q22;q21), resulting in the promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARA) fusion protein1 in 95% cases whereas variant translocations involving PLZF (11q23), NPM (5q35), NUMA (11q13) and STAT5b (17q23) account for the rest.2 Leukemias with PML-RARA translocations respond well to all-trans retinoic acid (ATRA) or arsenic trioxide (ATO) therapy3 whereas those with PLZF-RARA fusions respond poorly. Although primary resistance to ATRA is rare, secondary or acquired resistance is frequently observed in patients treated with ATRA alone or in combination with other chemotherapy regimens. However, molecular abnormalities mediating resistance to ATRA therapy are underexplored. Here, we report two cases of APL with RARA-PML deletions on der(17) or der(15), which displayed clinical evidence of primary and secondary resistance to therapy, respectively.

The patient achieved hematologic remission after treatment with ATRA and idarubicin. However, a bone marrow biopsy 30 days post-therapy showed dysplastic myeloid maturation and flow cytometry detected 2% blasts. Karyotype analysis showed 46,XY,t(15;17)(q22;q21)[6]/46,XY[14] and FISH with PML/RARA probes confirmed t(15;17) in 69.7% cells with a single fusion signal. These findings were consistent with primary resistance to therapy. After re-induction therapy with addition of ATO, the patient is currently in complete hematologic and cytogenetic remission.

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Authors and Affiliations

  1. Department of Pathology, Columbia University Medical Center, New York, NY, USA

    S Subramaniyam, S V Nandula, B Alobeid, G Bhagat & V V Murty

  2. Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA

    S Subramaniyam, S V Nandula & V V Murty

  3. Department of Medicine, Columbia University Medical Center, New York, NY, USA

    G Nichols

  4. Department of Pediatrics, Columbia University Medical Center, New York, NY, USA

    M Weiner & P Satwani

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  1. S Subramaniyam
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  2. S V Nandula
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  8. V V Murty
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Correspondence to V V Murty.

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Subramaniyam, S., Nandula, S., Nichols, G. et al. Do RARA/PML fusion gene deletions confer resistance to ATRA-based therapy in patients with acute promyelocytic leukemia?. Leukemia 20, 2193–2195 (2006). https://doi.org/10.1038/sj.leu.2404406

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