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PML–RARα ligand-binding domain deletion mutations associated with reduced disease control and outcome after first relapse of APL

Leukemia volume 24, pages 473–476 (2010)Cite this article

The promyelocytic leukemia retinoic acid receptor-α (PML–RARα) fusion gene is essential for both the initiation and perpetuation of acute promyelocytic leukemia (APL), and, consistent with its central pathogenic role, the effectiveness of all-trans retinoic acid (ATRA) and arsenic trioxide in the treatment of APL has been linked to the targeted destruction of PML–RARα.1 Over many years, adjustments of therapy with ATRA in combination with chemotherapy for the initial treatment of APL has achieved long-term remission rates, apparent disease cure, in ⩾85% of new APL patients.2 In two North American phase III clinical trials employing ATRA/chemotherapy (E2491 and C9710), mutations in the ligand-binding domain (LBD) of PML–RARα were found in 30–40% of the minority of patients who relapsed (see Gallagher et al.3 and Gallagher et al.4 and manuscript in preparation). In four of six patients from protocol E2491 who relapsed with LBD mutations, the APL clone harboring the mutation emerged and replaced the previously predominant wild-type PML–RARα APL cell population long after the last treatment with ATRA.3 These observations suggested that LBD mutation-harboring clones might selectively acquire ATRA-independent mechanism(s) of increased APL cell proliferation/survival competitiveness, and that this mechanism(s) might be favored in late relapse patients. In a collaborative effort to further explore this possibility, samples from previously reported late relapse patients, that is, relapse after >4 years,5 were not available; however, eight relapse samples from patients with a relatively long interval to first relapse (median, 1015 days after treatment on French–Belgian–Swiss APL group protocol, APL2000, or off-protocol in a similar manner),2 were available and were analyzed (Table 1). Notably, three patients found to have LBD mutations relapsed during ATRA maintenance therapy after a median of 530 days (range, 406–557 days), whereas five patients lacking LBD mutations relapsed long after the completion of ATRA therapy after a median of 1072 days (range, 992–1249 days). The latter observation suggests that the association of late-emerging LBD mutant clones, independent of proximate ATRA selection pressure, occurs less frequently than that suggested by the previous study (current, 0/5 cases versus reported, 4/6 cases3), which requires evaluation in a larger study. Further study is also required to assess whether different molecular mechanisms, and possibly different clinical consequences, are associated with LBD mutations that arise in APL clones that emerge relatively early while on ATRA therapy versus those that arise later off ATRA therapy.

Table 1 Vital data on eight relapse APL patients treated according to French–Belgian–Swiss APL group protocols: grouping by the absence or presence of PML–RARα mutations at first relapse
Full size table

More importantly, two of the three patients had mutations that produced deletions in the LBD of PML–RARα, including double mutant patient 6. In the latter patient, the chromatographic signal for the deletion-encoding transcript was stronger than the missense-encoding transcript (R267W), indicating that the deletion-harboring APL clone predominated at disease relapse (Figure 1a). This mutation was produced by defective mRNA splicing at the end of RARα exon 4, resulting in the insertion of 547 nucleotides of the succeeding RARα intron 4 sequence followed by aberrant splicing in the 3′-terminus of RARα (deletion=630 nucleotides). The incorporated intronic sequences introduced a stop codon 19 residues downstream from the insertion site, which was only 4 amino acids beyond the end of the DNA-binding domain of RARα (Figures 1a and d). Thus, at the transcript level, this was an insertion/truncation (ins/trn) mutation, but at the functional protein level, it involved an extensive deletion of the entire LBD as well as the more proximal hinge region that contains the Co-R box essential for corepressor protein binding (Δhinge-LBD).7 Unfortunately, neither relapse cells (needed to assess the effect on cell phenotype of this unprecedented mutant PML–RARα) nor genomic DNA (needed to determine the genetic basis of the mutation) was available. Of note, this patient as well as patient 8 with a double mutation had trisomy 8 before treatment (Table 1), which has been associated with either small genomic deletion mutations or copy number neutral loss of heterozygosity in APL.8 The other deletion mutation, Δ227 → 229 in patient 7, eliminated the codons for three amino acids with an in-frame shift to an alternative residue (ΔKFS/M; Figure 1b). This mutation was present in the less frequently affected proximal region of the LBD (Figure 1d).

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Acknowledgements

This work was supported in part by USPHS, NCI Grant R01-CA56771 (REG).

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Authors and Affiliations

  1. Department of Oncology, Montefiore Medical Center, Bronx, NY, USA

    E Schachter-Tokarz & R Gallagher

  2. Service d'Hématologie Clinique, Hôpital Avicenne AP-HP/Université Paris 13, Bobigny, France

    C Kelaidi & P Fenaux

  3. Unite de Biologie Cellulaire, AP-HP, Hôpital Saint-Louis, Paris, France

    B Cassinat & C Chomienne

  4. d'Hématologie Clinique, Hôpital Beaujon, Clichy, France

    C Gardin

  5. Department of Hematology, Hôpital Saint-Louis, Paris, France

    E Raffoux & H Dombret

  6. Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA

    R Gallagher

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Schachter-Tokarz, E., Kelaidi, C., Cassinat, B. et al. PML–RARα ligand-binding domain deletion mutations associated with reduced disease control and outcome after first relapse of APL. Leukemia 24, 473–476 (2010). https://doi.org/10.1038/leu.2009.220

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