Hypermethylation of specific microRNA genes in MLL-rearranged infant acute lymphoblastic leukemia: major matters at a micro scale.
MLL-rearranged acute lymphoblastic leukemia (ALL) in infants (<1 year) is the most aggressive type of childhood leukemia. To develop more suitable treatment strategies, a firm understanding of the biology underlying this disease is of utmost importance. MLL-rearranged ALL displays a unique gene expression profile, partly explained by erroneous histone modifications. We recently showed that t(4;11)-positive infant ALL is also characterized by pronounced promoter CpG hypermethylation. In this study, we investigated whether this widespread hypermethylation also affected microRNA (miRNA) expression. We identified 11 miRNAs that were downregulated in t(4;11)-positive infant ALL as a consequence of CpG hypermethylation. Seven of these miRNAs were re-activated after exposure to the de-methylating agent Zebularine. Interestingly, five of these miRNAs are associated either with MLL or MLL fusions, and for miR-152 we found both MLL and DNA methyltransferase 1 (DNMT1) as potential targeted genes. Finally, a high degree of methylation of the miR-152 CpG island was strongly correlated with a poor clinical outcome. Our data suggests that inhibitors of methylation have a potential beyond re-expression of hypermethylated protein-coding genes in t(4;11)-positive infant ALL. In this study, we provide additional evidence that they should be tested for their efficacy in MLL-rearranged infant ALL in in vivo models.
Department of Pediatric Oncology/Hematology, Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands.
D J P M
DJ
Stumpel
D
D
Schotte
E A M
EA
Lange-Turenhout
P
P
Schneider
L
L
Seslija
R X
RX
de Menezes
V E
VE
Marquez
R
R
Pieters
M L
ML
den Boer
R W
RW
Stam
D002880:Chromosomes, Human, Pair 11; D002894:Chromosomes, Human, Pair 4; D018899:CpG Islands; D003562:Cytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007223:Infant; D035683:MicroRNAs / Q000235:genetics*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D014178:Translocation, Genetic; D000074165:Zinc Finger E-box Binding Homeobox 2
C489832:HOXA3 protein, human; D018398:Homeodomain Proteins; C497422:KMT2A protein, human; C550856:MIRN152 microRNA, human; D035683:MicroRNAs; D012097:Repressor Proteins; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D051788:Myeloid-Lymphoid Leukemia Protein; D003562:Cytidine; C009131:pyrimidin-2-one beta-ribofuranoside; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; D011495:Histone-Lysine N-Methyltransferase