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APL, a model disease for cancer therapies?

Oncogene volume 20, pages 7136–7139 (2001)Cite this article

Only a few thousand new cases of Acute Promyelocytic Leukemia (APL) occur each year in the world. Contrasting with other acute myeloid leukemias, 80% of APL patients will be cured with molecules that are simple, highly effective and cheap. Why a special Oncogene issue? At least two particularities make this tumour unique. First, this disease, caused by a single illegitimate gene rearrangement, is one of the best-understood malignancies with respect to its molecular pathogenesis (Melnick and Licht, 1999). Second, molecules (e.g. all trans-retinoic acid (ATRA) and arsenic) that directly target the oncogenic product of the molecular defect (Quignon et al., 1997) are commonly used in clinical practice. The APL model, therefore, provides a striking example of oncogene-targeted cancer therapies. In contrast to the rational design of kinase inhibitors, therapeutic use of ATRA and arsenic in APL were found largely by chance. Understanding of their mechanism of action occurred after their clinical use, illustrating the role of privileged observations vs design in scientific breakthroughs.

APL was identified as a specific subset of myeloid leukemias in 1957. Up to 15 years ago, its clinical management remained a nightmare for physicians, due to the unpredictable onset of life-threatening bleeding disorders. From the 1970s, high doses of anthracyclins were shown to induce a significant number of remissions. Biology made its first appearance in 1984, with the identification of a highly specific chromosome translocation t(15;17) as a molecular hallmark of the disease. In 1986, the advent of ATRA as a differentiation therapy by the Shanghai group, opened a new era in the history of APL treatment (Huang et al., 1988). ZY Wang and L Degos review this therapeutic revolution, while C Chomienne analyses the effect of ATRA on primary APL cells ex vivo. In 1991, the first ATRA-responsive APL cell-line (NB4) was established (Lanotte et al., 1991). This unique cell-line bearing the t(15;17) translocation allowed ex vivo studies on APL cells, including the identification of several differentiation cross talks, as discussed by M Lanotte. That same year, the t(15;17) translocation was cloned and shown to encode a PML/RARα fusion protein, opening the molecular biology era of this disease. The role of RARα in myeloid differentiation is discussed by P Kastner and that of the various RARα fusion partners in APL pathogenesis by A Zelent and J Licht. Finally, in 1996, Arsenic trioxide (As2O3) was shown to be highly effective to induce remissions in untreated and even in ATRA-resistant relapse patients. ATRA therapy restores differentiation of the leukemic clone. In contrast, the contribution of differentiation versus apoptosis to disease remission upon As2O3 treatment is still unclear (see article by Z Chen). Remarkably, both ATRA and arsenic target the oncogenic PML/RARα fusion for activation/degradation, as discussed by H de Thé. This issue will attempt to summarize and put in perspective the findings of these last 10 years, which have lead to a surprising amount of discoveries of much broader implication than APL per se.

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Abbreviations

PML:

promyelocytic leukemia

APL:

acute promyelocytic leukemia

NBs:

nuclear bodies

ATRA:

all trans retinoic acid

As2O3:

arsenic trioxide

PLZF:

promyelocytic zinc finger

RAR:

retinoic acid receptor

IFN:

interferon

SUMO:

small ubiquitin modifier

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Acknowledgements

We warmly thank all colleagues who agreed to participate in the making of this issue, in particular M Lanotte for the resistant NB4 nomenclature and P Freemont for the PML isoforms nomenclature and all colleagues for consenting to use these nomenclatures.

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Authors and Affiliations

  1. CNRS UPR 9051 Hôpital St. Louis 1, avenue C. Vellefaux, Paris Cedex, 75475, 10, France

    Hugues de Thé

  2. CNRS UPR 9045 Institut André Lwoff 7, rue Guy Moquet, Villejuif Cedex, 94801, France

    Mounira K Chelbi-Alix

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  1. Hugues de Thé
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Correspondence to Hugues de Thé or Mounira K Chelbi-Alix.

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de Thé, H., Chelbi-Alix, M. APL, a model disease for cancer therapies?. Oncogene 20, 7136–7139 (2001). https://doi.org/10.1038/sj.onc.1204851

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