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Eradication of acute promyelocytic leukemia-initiating cells by PML/RARA-targeting

  • Progress in Hematology
  • Molecular pathogenesis of leukemia and leukemia stem cells
  • Published:
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Abstract

Acute promyelocytic leukemia (APL) is characterized by a t(15;17) translocation that yields a PML/RARA fusion protein. Expression of PML/RARA, a potent transcriptional repressor, induces APL in mice. Both retinoic acid (RA) and arsenic trioxide directly target PML/RARA-mediated transcriptional repression and protein stability, inducing rapid differentiation of the promyelocytes and clinical remission in most APL patients. RA also triggers growth arrest and progressive clearance of leukemia initiating cells (LIC), both ex vivo and in vivo. Suboptimal RA concentrations or expression of the PLZF/RARA variant allows complete RA-induced differentiation, but neither LIC clearance nor disease remission. Thus, RA-induced differentiation and LIC clearance may be uncoupled. The RA/arsenic trioxide association, which dramatically synergizes for PML/RARA degradation but not for differentiation, rapidly clears LIC in a proteasome-dependent manner, resulting in APL eradication in murine models and patients. Collectively, these results demonstrate that LIC clearance, which mirrors PML/RARA degradation, is the primary basis for APL cure by the RA/arsenic trioxide association, rather than differentiation. Oncogene degradation could be a generally applicable therapeutic strategy to clear LICs in several types of tumors.

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  1. Department of Internal Medicine, American University of Beirut, Beirut, Lebanon

    Rihab Nasr

  2. Hôpital St. Louis, Service de Biochimie, Equipe labellisée Ligue Nationale Contre le Cancer, INSERM/CNRS/Université de Paris 7 UMR 944/7212, 1, Av. C. Vellefaux, 75475, Paris Cedex 10, France

    Hugues de Thé

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Correspondence to Hugues de Thé.

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Nasr, R., de Thé, H. Eradication of acute promyelocytic leukemia-initiating cells by PML/RARA-targeting. Int J Hematol 91, 742–747 (2010). https://doi.org/10.1007/s12185-010-0582-0

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