In vivo analysis of the molecular pathogenesis of acute promyelocytic leukemia in the mouse and its therapeutic implications Journal Article
| Authors: | He, L. Z.; Merghoub, T.; Pandolfi, P. P. |
| Article Title: | In vivo analysis of the molecular pathogenesis of acute promyelocytic leukemia in the mouse and its therapeutic implications |
| 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. |
| Keywords: | gene translocation; review; interferon; nonhuman; antineoplastic agents; animals; mice; gene expression; interleukin 4; neoplasm proteins; cell differentiation; enzyme inhibitor; cancer model; transgenic mouse; cancer genetics; arsenic trioxide; leukemia, promyelocytic, acute; cytokine; drug antagonism; drug mechanism; leukemogenesis; acute myeloblastic leukemia; fusion gene; oncogene proteins, fusion; remission; chromosome translocation; disease models, animal; granulocyte colony stimulating factor; retinoic acid; hydroxamic acid; chromosome 17; granulocyte; transgenic mice; histone deacetylase; trichostatin a; tumor necrosis factor; chimeric protein; interleukin 1; promyelocyte; retinoic acid receptor; tretinoin; apl; antileukemic agent; butyric acid derivative; humans; human; priority journal; short chain fatty acid; hdaci; cancer differentiation therapy |
| Journal Title: | Oncogene |
| Volume: | 18 |
| Issue: | 38 |
| ISSN: | 0950-9232 |
| Publisher: | Nature Publishing Group |
| Date Published: | 1999-09-20 |
| Start Page: | 5278 |
| End Page: | 5292 |
| Language: | English |
| DOI: | 10.1038/sj.onc.1203088 |
| PUBMED: | 10498880 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Review -- Export Date: 16 August 2016 -- Source: Scopus |
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