In vivo analysis of the role of aberrant histone deacetylase recruitment and RARα blockade in the pathogenesis of acute promyelocytic leukemia

Hiromichi Matsushita, Pier Paolo Scaglioni, Mantu Bhaumik, Eduardo M. Rego, Fan Cai Lu, Samia M. Majid, Hayato Miyachi, Akira Kakizuka, Wilson H. Miller, Pier Paolo Pandolfi

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Abstract

The promyelocytic leukemia-retinoic acid receptor α (PML-RARα) protein of acute promyelocytic leukemia (APL) is oncogenic in vivo. It has been hypothesized that the ability of PML-RARα to inhibit RARα 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-RARα 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 RARα mutants, as well as that of PML-RARα mutants that are insensitive to retinoic acid. Surprisingly, although HDAC1-RARα did act as a bonafide DN RARα mutant in cellular in vitro and in cell culture, this fusion protein, as well as other DN RARα 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..α 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.

Original languageEnglish (US)
Pages (from-to)821-828
Number of pages8
JournalJournal of Experimental Medicine
Volume203
Issue number4
DOIs
StatePublished - Apr 17 2006

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Acute Promyelocytic Leukemia
Histone Deacetylases
Transgenic Mice
Retinoic Acid Receptors
Leukemia
Proteins
Chromatin Assembly and Disassembly
Cell Fusion
Tretinoin
Cell Culture Techniques
In Vitro Techniques

ASJC Scopus subject areas

  • Immunology

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In vivo analysis of the role of aberrant histone deacetylase recruitment and RARα blockade in the pathogenesis of acute promyelocytic leukemia. / Matsushita, Hiromichi; Scaglioni, Pier Paolo; Bhaumik, Mantu; Rego, Eduardo M.; Lu, Fan Cai; Majid, Samia M.; Miyachi, Hayato; Kakizuka, Akira; Miller, Wilson H.; Pandolfi, Pier Paolo.

In: Journal of Experimental Medicine, Vol. 203, No. 4, 17.04.2006, p. 821-828.

Research output: Contribution to journalArticle

Matsushita, Hiromichi ; Scaglioni, Pier Paolo ; Bhaumik, Mantu ; Rego, Eduardo M. ; Lu, Fan Cai ; Majid, Samia M. ; Miyachi, Hayato ; Kakizuka, Akira ; Miller, Wilson H. ; Pandolfi, Pier Paolo. / In vivo analysis of the role of aberrant histone deacetylase recruitment and RARα blockade in the pathogenesis of acute promyelocytic leukemia. In: Journal of Experimental Medicine. 2006 ; Vol. 203, No. 4. pp. 821-828.
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