In vivo analysis of the role of aberrant histone deacetylase recruitment and RAR alpha blockade in the pathogenesis of acute promyelocytic leukemia.
The promyelocytic leukemia-retinoic acid receptor alpha (PML-RARalpha) protein of acute promyelocytic leukemia (APL) is oncogenic in vivo. It has been hypothesized that the ability of PML-RARalpha to inhibit RARalpha 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-RARalpha 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 RARalpha mutants, as well as that of PML-RARalpha mutants that are insensitive to retinoic acid. Surprisingly, although HDAC1-RARalpha did act as a bona fide DN RARalpha mutant in cellular in vitro and in cell culture, this fusion protein, as well as other DN RARalpha 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 RARalpha 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.
Cancer Biology and Genetics Program, Department of Pathology, Weill Graduate School of Medical Sciences, Cornell University, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Hiromichi
H
Matsushita
Pier Paolo
PP
Scaglioni
Mantu
M
Bhaumik
Eduardo M
EM
Rego
Lu Fan
LF
Cai
Samia M
SM
Majid
Hayato
H
Miyachi
Akira
A
Kakizuka
Wilson H
WH
Miller
Pier Paolo
PP
Pandolfi
D000818:Animals; D002460:Cell Line; D006655:Histone Deacetylases / Q000378:metabolism*; D015473:Leukemia, Promyelocytic, Acute / Q000201:enzymology* / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D000071156:Promyelocytic Leukemia Protein; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology
D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D006655:Histone Deacetylases