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| In vivo analysis of the molecular pathogenesis of acute promyelocytic leukemia in the mouse and its therapeutic implications |
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| Author(s): He LZ, Merghoub T, Pandolfi PP |
| Source: ONCOGENE Volume: 18 Issue: 38 Pages: 5278-5292 Published: SEP 20 1999 |
| Times Cited: 77 References: 119 |
| 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 alpha (RAR alpha) gene on chromosome 17. As a consequence of the translocation RAR alpha variably fuses to the PML, PLZF, NPM and NUMA genes (X genes), leading to the generation of RAR alpha-X and X-RAR alpha 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 RAR alpha and the PLZF genes (PLZF-RAR alpha) 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 veil as in human APL patients novel therapeutic strategies. |
| Document Type: Review |
| Language: English |
| Reprint Address: Pandolfi, PP (reprint author), Cornell Univ, Grad Sch Med Sci, Mem Sloan Kettering Canc Ctr, Sloan Kettering Div,Dept Human Genet, 1273 York Ave, New York, NY 10021 USA |
Addresses:
1. Cornell Univ, Grad Sch Med Sci, Mem Sloan Kettering Canc Ctr, Sloan Kettering Div,Dept Human Genet, New York, NY 10021 USA
2. Cornell Univ, Grad Sch Med Sci, Mem Sloan Kettering Canc Ctr, Sloan Kettering Div,Mol Biol Program, New York, NY 10021 USA |
| Publisher: STOCKTON PRESS, HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND |
| Subject Category: Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity |
| IDS Number: 240CP |
| ISSN: 0950-9232 |
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