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Relapse of acute promyelocytic leukemia with PML-RARα mutant subclones independent of proximate all-trans retinoic acid selection pressure

Leukemia volume 20, pages 556–562 (2006)Cite this article

Abstract

Relapse of acute promyelocytic leukemia (APL) following all-trans retinoic acid (ATRA) therapy has been associated with the acquisition of mutations in the high-affinity ATRA binding site in PML-RARα, but little information is available about the selection dynamics of the mutation-harboring subclones. In this study, 6/18 patients treated with sequential ATRA and chemotherapy on protocol INT0129 relapsed with complete replacement of the nonmutant pretreatment APL cell population by a PML-RARα mutant subclone. Two patients relapsed in proximity of ATRA treatment; however, in four patients there was a 6–48 month hiatus between the last ATRA treatment and relapse. The mutant subclones were not detectable in samples tested ⩾3 months before relapse at ⩾1 in 102 (10−2) sensitivity. In one patient, a functionally weak mutation was detected at 10−4 sensitivity before therapy but only limited pre-relapse enrichment of the mutant subclone was observed on subsequent ATRA therapy. These results indicate that proximate ATRA selection pressure is frequently not the main determinant for the emergence of strongly dominant PML-RARα mutant subclones and suggest that APL subclones harboring PML-RARα mutations are predisposed to the acquisition of secondary genetic/epigenetic alterations that result in a growth/survival advantage.

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Acknowledgements

We express our gratitude to staff and patients from ECOG-, SWOG-, and CALGB-affiliated institutions for their cooperation in providing clinical specimens and information. We especially thank Drs M Tallman and P Wiernik, ECOG, co-chairpersons of protocol INT0129; and group protocol chairpersons, Dr F Appelbaum, SWOG, and Dr C Bloomfield, CALGB. This work was supported by Grants CA56771 and CA21115 from the National Institutes of Health.

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Authors and Affiliations

  1. Departments of Oncology and Medicine, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY, USA

    R E Gallagher, E L Schachter-Tokarz, D-C Zhou, W Ding, S H Kim & B J Sankoorikal

  2. Applied Biosystems Inc., Foster City, CA, USA

    W Bi & K J Livak

  3. Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA

    J L Slack

  4. Departments of Pathology and Cell Biology, University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA

    C L Willman

Authors
  1. R E Gallagher
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  2. E L Schachter-Tokarz
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  3. D-C Zhou
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  4. W Ding
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  5. S H Kim
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  6. B J Sankoorikal
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  7. W Bi
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  8. K J Livak
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  9. J L Slack
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  10. C L Willman
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Correspondence to R E Gallagher.

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Gallagher, R., Schachter-Tokarz, E., Zhou, DC. et al. Relapse of acute promyelocytic leukemia with PML-RARα mutant subclones independent of proximate all-trans retinoic acid selection pressure. Leukemia 20, 556–562 (2006). https://doi.org/10.1038/sj.leu.2404118

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