TY - JOUR
T1 - In vivo analysis of the role of aberrant histone deacetylase recruitment and RARα blockade in the pathogenesis of acute promyelocytic leukemia
AU - Matsushita, Hiromichi
AU - Scaglioni, Pier Paolo
AU - Bhaumik, Mantu
AU - Rego, Eduardo M.
AU - Lu, Fan Cai
AU - Majid, Samia M.
AU - Miyachi, Hayato
AU - Kakizuka, Akira
AU - Miller, Wilson H.
AU - Pandolfi, Pier Paolo
PY - 2006/4/17
Y1 - 2006/4/17
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33645873584&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33645873584&partnerID=8YFLogxK
U2 - 10.1084/jem.20050616
DO - 10.1084/jem.20050616
M3 - Article
C2 - 16549595
AN - SCOPUS:33645873584
SN - 0022-1007
VL - 203
SP - 821
EP - 828
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 4
ER -