In vivo analysis of the molecular pathogenesis of acute promyelocytic leukemia in the mouse and its therapeutic implications.
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 alpha (RARalpha) gene on chromosome 17. As a consequence of the translocation RARalpha variably fuses to the PML, PLZF, NPM and NUMA genes (X genes), leading to the generation of RARalpha-X and X-RARalpha 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 RARalpha and the PLZF genes (PLZF-RARalpha) 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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Department of Human Genetics and Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Division, Graduate School of Medical Sciences, Cornell University, 1275 York Avenue, New York, NY 10021, USA.
Merghoub
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Pandolfi
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D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D004195:Disease Models, Animal; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics*; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D014212:Tretinoin / Q000627:therapeutic use
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin