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In vivo analysis of the molecular pathogenesis of acute promyelocytic leukemia in the mouse and its therapeutic implications

Oncogene volume 18, pages 5278–5292 (1999)Cite this article

Abstract

Acute promyelocytic leukemia (APL) is characterized by the expansion of malignant myeloid cells blocked at the promyelocytic stage of hemopoietic development, and is associated with reciprocal chromosomal translocations always involving the retinoic acid receptor α (RARα) gene on chromosome 17. As a consequence of the translocation RARα variably fuses to the PML, PLZF, NPM and NUMA genes (X genes), leading to the generation of RARα-X and X-RARα fusion genes. The aberrant chimeric proteins encoded by these genes may exert a crucial role in leukemogenesis. Retinoic acid (RA), a metabolite of vitamin A, can overcome the block of maturation at the promyelocytic stage and induce the malignant cells to terminally mature into granulocytes resulting in complete albeit transient disease remission. APL has become, for this reason, the paradigm for ‘cancer differentiation therapy’. Furthermore, APL associated with translocation between the RARα and the PLZF genes (PLZF-RARα) shows a distinctly worse prognosis with poor response to chemotherapy and little or no response to treatment with RA, thus defining a new APL syndrome. Here we will focus our attention on the recent progresses made in defining the molecular mechanisms underlying the pathogenesis of this paradigmatic disease in vivo in the mouse. We will review the critical contribution of mouse modeling in unraveling the transcriptional basis for the differential response to RA in APL. We will also discuss how this new understanding has allowed to propose, develop and test in these murine leukemia models as well as in human APL patients novel therapeutic strategies.

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Acknowledgements

We would like to thank all the past and present members of the laboratory of Molecular and Developmental Biology (MADB) lab at Memorial Sloan-Kettering Cancer Center, working on APL and related subjects: Maria Barna, Mantu Bhaumik, Laurent Delva, Mirella Gaboli, Domenica Gandini, Marco Giorgio, Ailan Guo, Nicola Hawe, Sundeep Kalantry, Daniela Peruzzi, Eduardo Rego, Roberta Rivi, Simona Ronchetti, Davide Ruggero, Paolo Salomoni, Carla Tribioli, Zhu-Gang Wang, Hui Zhang, Sue Zhong as well as Letizia Longo in our Department. L-Z He was partially supported by the Charles H Revson Foundation. PP Pandolfi is a Scholar of the Leukemia Society of America. Our work is supported, by the NCI, the De Witt Wallace Fund for Memorial Sloan-Kettering Cancer Center, and NIH Grants to PP Pandolfi.

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  1. Department of Human Genetics and Molecular Biology Program, Sloan-Kettering Division, Memorial Sloan-Kettering Cancer Center, Graduate School of Medical Sciences, Cornell University, 1275 York Avenue, New York, NY 10021, USA

    Li-Zhen He, Taha Merghoub & Pier Paolo Pandolfi

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He, LZ., Merghoub, T. & Pandolfi, P. In vivo analysis of the molecular pathogenesis of acute promyelocytic leukemia in the mouse and its therapeutic implications. Oncogene 18, 5278–5292 (1999). https://doi.org/10.1038/sj.onc.1203088

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