In vivo analysis of the role of aberrant histone deacetylase recruitment and RAR alpha blockade in the pathogenesis of acute promyelocytic leukemia Journal Article
| Authors: | Matsushita, H.; Scaglioni, P. P.; Bhaumik, M.; Rego, E. M.; Cai, L. F.; Majid, S. M.; Miyachi, H.; Kakizuka, A.; Miller, W. H.; Pandolfi, P. P. |
| Article Title: | In vivo analysis of the role of aberrant histone deacetylase recruitment and RAR alpha blockade in the pathogenesis of acute promyelocytic leukemia |
| Abstract: | The promyelocytic leukemia - retinoic acid receptor alpha (PML-RAR alpha) protein of acute promyelocytic leukemia (APL) is oncogenic in vivo. It has been hypothesized that the ability of PML-RAR alpha to inhibit RAR alpha function through PML-dependent aberrant recruitment of histone deacetylases (HDACs) and chromatin remodeling is the key initiating event for leukemogenesis. To elucidate the role of HDAC in this process, we have generated HDAC1-RAR alpha fusion proteins and tested their activity and oncogenicity in vitro and in vivo in transgenic mice (TM). In parallel, we studied the in vivo leukemogenic potential of dominant negative (DN) and truncated RAR alpha mutants, as well as that of PML-RAR alpha mutants that are insensitive to retinoic acid. Surprisingly, although HDAC1-RAR alpha did act as a bona fide DN RAR alpha mutant in cellular in vitro and in cell culture, this fusion protein, as well as other DN RAR alpha mutants, did not cause a block in myeloid differentiation in vivo in TM and were not leukemogenic. Comparative analysis of these TM and of TM/PML-/- and p53(-/-) compound mutants lends support to a model by which the RAR alpha and PML blockade is necessary, but not sufficient, for leukemogenesis and the PML domain of the fusion protein provides unique functions that are required for leukemia initiation. |
| Keywords: | proteins; transgenic mice; differentiation; fusion; binding; inhibition; homodimers; chromosomal-abnormalities; co-repressor; acid receptor; pml protein |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 203 |
| Issue: | 4 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2006-04-17 |
| Start Page: | 821 |
| End Page: | 828 |
| Language: | English |
| ACCESSION: | WOS:000237056000006 |
| DOI: | 10.1084/jem.20050616 |
| PROVIDER: | wos |
| PMCID: | PMC2118271 |
| PUBMED: | 16549595 |
| Notes: | --- - Article - "Source: Wos" |
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