MLL-AF9-Induced Leukemogenesis Requires Coexpression of the Wild-Type Mll Allele

Thiel, Austin; Blessington, Peter; Zou, Tong; Feather, Danielle; Wu, Xuehang; Yan, Jizhou; Zhang, Hui; Liu, Zuguo; Ernst, Patricia; Koretzky, Gary A.; Hua, Xianxin

doi:10.1016/j.ccr.2009.12.034

Cited by 213 publications

(215 citation statements)

References 48 publications

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“…36 Whether wild-type MLL is also required for the development or maintenance of t(4;11)-positive leukemias remains uncertain. However, as we show in this study, epigenetic inactivation of miR-152 at least prevents the downregulation of wild-type MLL.…”

Section: Discussionmentioning

confidence: 99%

Hypermethylation of specific microRNA genes in MLL-rearranged infant acute lymphoblastic leukemia: major matters at a micro scale

et al. 2010

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MLL-rearranged acute lymphoblastic leukemia (ALL) in infants (o1 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.

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Section: Discussionmentioning

confidence: 99%

Hypermethylation of specific microRNA genes in MLL-rearranged infant acute lymphoblastic leukemia: major matters at a micro scale

et al. 2010

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“…84 MLL wild-type, AF4-MLL and DNMT1 were identified as potential target genes for miR-152 based on 3 0 UTR sequence homology. 79 This is of high interest because the co-expression of MLL wild-type is facilitating MLL-AF9-induced leukemogenesis 85 and the AF4-MLL reciprocal fusion protein contributes to leukemic transformation. 86 Moreover high levels of DNMT1 may be responsible for the genome-wide hypermethylation that characterizes t(4;11)/AF4-MLL-positive ALL and was linked to an increased risk of relapse.…”

Section: Using Epigenetic Drugsmentioning

confidence: 99%

MicroRNAs in acute leukemia: from biological players to clinical contributors

2011

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MicroRNAs (miRNAs) are involved in the management of hematopoiesis. As a consequence, miRNA dysregulation causes disruption of the hematopoietic system and leukemia may arise. We here comprehensively discuss miRNAs found discriminative for cytogenetic and molecular subtypes of acute leukemia. These miRNAs are either known miRNAs involved in leukemogenesis with proven tumor suppressor or oncogenic activities or are newly identified by high-throughput sequencing with yet unknown function. Furthermore, forces are outlined that drive aberrant miRNA function, which include genetic abnormalities (for example, deletions, translocations and mutations) and epigenetic aberrations (for example, aberrant DNA methylation or histone modifications). Interestingly, leukemia-silenced miRNAs can be re-expressed upon treatment with de-methylating agents. Targeting miRNA expression may serve a therapeutical role, albeit at present this way of targeted therapy is in its infancy. However, emerging knowledge about the biology of miRNAs in leukemia may result into a role for these miRNAs in the diagnosis and treatment of acute leukemia.

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“…Further studies indicate that the wild-type MLL allele is required for MLL-AF9-induced leukemogenesis. Wild-type MLL controls both H3K4 methylation and MLL-AF9-induced H3K79 methylation (Thiel et al, 2010). Aggressive histone modifications in 5 0 Hoxa cluster gene expression (Yan et al, 2006a) and promoter DNA methylation (Bullinger and Armstrong, 2010) substantially contribute to leukemic cell phenotypes.…”

Section: Failure Of Maintenance Of Hox Genes In Leukemia Cellsmentioning

confidence: 99%

“…Increasing evidence suggests that Hox transcription factors play a definitive role in normal proliferation and differentiation of hematopoietic cells (Magli et al, 1997;Owens and Hawley, 2002). Recent discoveries revealed that the menin and MLL-containing histone methyltransferase complex is required for Hox gene-dependent proliferation and differentiation of hematopoietic progenitors and leukemia stem cells (Hess, 2004;Hughes et al, 2004;Milne et al, 2005;Yokoyama et al, 2005Yokoyama et al, , 2010Chen et al, 2006;Thiel et al, 2010). These studies have given emphasis to epigenetic regulations in Hox-dependent hematopoiesis and leukemogenesis.…”

Section: Introductionmentioning

confidence: 99%