TY - JOUR
T1 - DNA methylation-independent loss of RARA gene expression in acute myeloid leukemia
AU - Glasow, Annegret
AU - Barrett, Angela
AU - Petrie, Kevin
AU - Gupta, Rajeev
AU - Boix-Chornet, Manuel
AU - Zhou, Da-Cheng
AU - Grimwade, David
AU - Gallagher, Robert
AU - von Lindern, Marieke
AU - Waxman, Samuel
AU - Enver, Tariq
AU - Hildebrandt, Guido
AU - Zelent, Arthur
PY - 2008
Y1 - 2008
N2 - The retinoic acid receptor (RAR) alpha gene (RARA) encodes 2 major isoforms and mediates positive effects of all-trans retinoic acid (ATRA) on myelomonocytic differentiation. Expression of the ATRA-inducible (RARalpha2) isoform increases with myelomonocytic differentiation and appears to be down-regulated in many acute myeloid leukemia (AML) cell lines. Here, we demonstrate that relative to normal myeloid stem/progenitor cells, RARalpha2 expression is dramatically reduced in primary AML blasts. Expression of the RARalpha1 isoform is also significantly reduced in primary AML cells, but not in AML cell lines. Although the promoters directing expression of RARalpha1 and RARalpha2 are respectively unmethylated and methylated in AML cell lines, these regulatory regions are unmethylated in all the AML patient cell samples analyzed. Moreover, in primary AML cells, histones associated with the RARalpha2 promoter possessed diminished levels of H3 acetylation and lysine 4 methylation. These results underscore the complexities of the mechanisms responsible for deregulation of gene expression in AML and support the notion that diminished RARA expression contributes to leukemogenesis
AB - The retinoic acid receptor (RAR) alpha gene (RARA) encodes 2 major isoforms and mediates positive effects of all-trans retinoic acid (ATRA) on myelomonocytic differentiation. Expression of the ATRA-inducible (RARalpha2) isoform increases with myelomonocytic differentiation and appears to be down-regulated in many acute myeloid leukemia (AML) cell lines. Here, we demonstrate that relative to normal myeloid stem/progenitor cells, RARalpha2 expression is dramatically reduced in primary AML blasts. Expression of the RARalpha1 isoform is also significantly reduced in primary AML cells, but not in AML cell lines. Although the promoters directing expression of RARalpha1 and RARalpha2 are respectively unmethylated and methylated in AML cell lines, these regulatory regions are unmethylated in all the AML patient cell samples analyzed. Moreover, in primary AML cells, histones associated with the RARalpha2 promoter possessed diminished levels of H3 acetylation and lysine 4 methylation. These results underscore the complexities of the mechanisms responsible for deregulation of gene expression in AML and support the notion that diminished RARA expression contributes to leukemogenesis
U2 - https://doi.org/10.1182/blood-2007-05-088344
DO - https://doi.org/10.1182/blood-2007-05-088344
M3 - Article
C2 - 17993618
SN - 0006-4971
VL - 111
SP - 2374
EP - 2377
JO - Blood
JF - Blood
IS - 4
ER -