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Acute myeloid leukemia

Early and sensitive detection of PML-A216V mutation by droplet digital PCR in ATO-resistant acute promyelocytic leukemia

Leukemia volume 33, pages 1527–1530 (2019)Cite this article

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Treatment outcomes in patients with newly diagnosed acute promyelocytic leukemia (APL) has dramatically improved in the past two decades, following the advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). ATRA combined with chemotherapy (CHT) results in cure rates above 80%; however, it is associated with significant short- and long-term toxicity, including the risk of secondary leukemias. ATO combined with ATRA is significantly more active than conventional CHT in APL [1, 2], and has more manageable toxic effects. Despite these advances, mechanisms of resistance to ATRA-CHT and to ATRA-ATO, although infrequent, remain elusive.

Recent investigations, including one from our group [3], suggested that the presence of point mutations in the two moieties of the PML/RARA hybrid may play a role in resistance to therapy. In keeping with this hypothesis, mutations of the PML-B2 domain of PML/RARA have been shown to prevent ATO binding, inhibiting degradation of the oncoprotein, thus hindering oligomerization into nuclear bodies [4]. In particular, the PML-A216V mutation, the most commonly described in the PML-B2 domain, is known to confer resistance to ATO [4, 5]. We developed and tested a droplet digital PCR (ddPCR) assay for sensitive detection of the PML-A216V mutation, as a tool for early prediction of ATO resistance in relapsed APL patients. Using this technology, we tested 13 APL patients, who relapsed after ATRA-ATO combinations. The main clinical and biological characteristics of patients are shown in Table 1.

Table 1 Clinical and biological characteristics of APL patients
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References

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Acknowledgements

This work was supported by Associazione italiana contro le Leucemie-Linfomi e Mieloma (AIL) (to LI), Associazione Italiana Ricerca sul Cancro (AIRC, IG No. 16952 to MTV), AIRC 5 × 1000 call "Metastatic disease: the keyunmet need in oncology" to MYNERVA project, and IG No. 21267 to FLC (MYeloid NEoplasms Research Venture Airc). A detailed description of the MYNERVA project is available at http://www.progettoagimm.it.

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  1. These authors contributed equally: V. Alfonso, L. Iaccarino

Authors and Affiliations

  1. Department of Biomedicine and Prevention, University of Tor Vergata, Rome, Italy

    V. Alfonso, L. Iaccarino, T. Ottone, L. Cicconi, S. Lavorgna, M. Divona, A. Cristiano, C. Ciardi, S. Travaglini, G. Falconi, A. Venditti, W. Arcese, M. T. Voso & F. Lo-Coco

  2. Neuroimmunology and Flow Cytometry Units, Fondazione Santa Lucia-I.R.C.C.S, Rome, Italy

    T. Ottone, S. Lavorgna & F. Lo-Coco

  3. Division of Hematology, Niguarda Hospital, Milan, Italy

    R. Cairoli

  4. CRI Lab 2, ACTREC, Homi Bhabha National Institute, Mumbai, India

    S. K. Hasan

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  1. V. Alfonso
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  2. L. Iaccarino
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  3. T. Ottone
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  4. L. Cicconi
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  7. R. Cairoli
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  13. A. Venditti
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  14. W. Arcese
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  15. M. T. Voso
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  16. F. Lo-Coco
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Correspondence to F. Lo-Coco.

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Alfonso, V., Iaccarino, L., Ottone, T. et al. Early and sensitive detection of PML-A216V mutation by droplet digital PCR in ATO-resistant acute promyelocytic leukemia. Leukemia 33, 1527–1530 (2019). https://doi.org/10.1038/s41375-018-0298-3

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