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

¹ Cancer Biology and Genetics Program, Department of Pathology and ² Department of Medicine, Weill Graduate School of Medical Sciences, Cornell University, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
³ Department of Laboratory Medicine, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan
⁴ Laboratory of Functional Biology, Kyoto University Graduate School of Biostudies, Kyoto 606-8501, Japan
⁵ Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Quebec H3T 1E2, Canada

CORRESPONDENCE Pier Paolo Pandolfi: p-pandolfi{at}ski.mskcc.org

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

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