TY - JOUR
T1 - Identification of genes transcriptionally responsive to the loss of MLL fusions in MLL-rearranged acute lymphoblastic leukemia
AU - Van Der Linden, Marieke H.
AU - Seslija, Lidija
AU - Schneider, Pauline
AU - Driessen, Emma M.C.
AU - Castro, Patricia Garrido
AU - Stumpel, Dominique J.P.M.
AU - Van Roon, Eddy
AU - De Boer, Jasper
AU - Williams, Owen
AU - Pieters, Rob
AU - Stam, Ronald W.
N1 - Publisher Copyright:
© 2015 van der Linden et al.
PY - 2015/3/20
Y1 - 2015/3/20
N2 - MLL-rearranged acute lymphoblastic leukemia (ALL) in infants (<1 year) is characterized by high relapse rates and a dismal prognosis. To facilitate the discovery of novel therapeutic targets, we here searched for genes directly influenced by the repression of various MLL fusions. Methods For this, we performed gene expression profiling after siRNA-mediated repression of MLLAF4, MLL-ENL, and AF4-MLL in MLL -rearranged ALL cell line models. The obtained results were compared with various already established gene signatures including those consisting of known MLL-AF4 target genes, or those associated with primary MLL-rearranged infant ALL samples. Results Genes that were down-regulated in response to the repression of MLL-AF4 and MLL-ENL appeared characteristically expressed in primary MLL-rearranged infant ALL samples, and often represented known MLL-AF4 targets genes. Genes that were up-regulated in response to the repression of MLL-AF4 and MLL-ENL often represented genes typically silenced by promoter hypermethylation in MLL-rearranged infant ALL. Genes that were affected in response to the repression of AF4-MLL showed significant enrichment in gene expression profiles associated with AF4-MLL expressing t(4;11)+ infant ALL patient samples We conclude that the here identified genes readily responsive to the loss of MLL fusion expression potentially represent attractive therapeutic targets and may provide additional insights in MLL-rearranged acute leukemias.
AB - MLL-rearranged acute lymphoblastic leukemia (ALL) in infants (<1 year) is characterized by high relapse rates and a dismal prognosis. To facilitate the discovery of novel therapeutic targets, we here searched for genes directly influenced by the repression of various MLL fusions. Methods For this, we performed gene expression profiling after siRNA-mediated repression of MLLAF4, MLL-ENL, and AF4-MLL in MLL -rearranged ALL cell line models. The obtained results were compared with various already established gene signatures including those consisting of known MLL-AF4 target genes, or those associated with primary MLL-rearranged infant ALL samples. Results Genes that were down-regulated in response to the repression of MLL-AF4 and MLL-ENL appeared characteristically expressed in primary MLL-rearranged infant ALL samples, and often represented known MLL-AF4 targets genes. Genes that were up-regulated in response to the repression of MLL-AF4 and MLL-ENL often represented genes typically silenced by promoter hypermethylation in MLL-rearranged infant ALL. Genes that were affected in response to the repression of AF4-MLL showed significant enrichment in gene expression profiles associated with AF4-MLL expressing t(4;11)+ infant ALL patient samples We conclude that the here identified genes readily responsive to the loss of MLL fusion expression potentially represent attractive therapeutic targets and may provide additional insights in MLL-rearranged acute leukemias.
UR - http://www.scopus.com/inward/record.url?scp=84925864748&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0120326
DO - 10.1371/journal.pone.0120326
M3 - Article
C2 - 25793396
AN - SCOPUS:84925864748
SN - 1932-6203
VL - 10
JO - PLoS ONE
JF - PLoS ONE
IS - 3
M1 - e0120326
ER -