Leukaemogenesis: more than mutant genes

Chen, Jianjun; Odenike, Olatoyosi; Rowley, Janet D.

doi:10.1038/nrc2765

Cited by 286 publications

(235 citation statements)

References 188 publications

(214 reference statements)

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“…Although large-scale, global miRNA expression profiling assays have reported the correlation of signatures of many miRNAs with cytogenetic and molecular subtypes of acute leukemia, as well as patient response to treatment (16,(30)(31)(32)(33)(34)(35)(36)(37), the mechanisms underlying the deregulation of and the function of individual miRNAs in acute leukemia are largely unknown (7).…”

Section: Discussionmentioning

confidence: 99%

“…Rapidly accumulating evidence has revealed that miRNAs are strongly associated with cancer (3,(5)(6)(7). Recent studies suggest that a cluster of miRNAs, the miR-17-92 polycistron located at 13q31 [containing seven individual miRNAs including miR-17-5p (now named miR-17), miR-17-3p (now named miR-17*), miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-92a-1], may function as an oncogene (8)(9)(10)(11)(12).…”

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confidence: 99%

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Aberrant overexpression and function of the miR-17-92 cluster in MLL -rearranged acute leukemia

Mi¹,

Li²,

Chen³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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138

125

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MicroRNA (miRNA)-17-92 cluster (miR-17-92), containing seven individual miRNAs, is frequently amplified and overexpressed in lymphomas and various solid tumors. We have found that it is also frequently amplified and the miRNAs are aberrantly overexpressed in mixed lineage leukemia (MLL)-rearranged acute leukemias. Furthermore, we show that MLL fusions exhibit a much stronger direct binding to the locus of this miRNA cluster than does wild-type MLL; these changes are associated with elevated levels of histone H3 acetylation and H3K4 trimethylation and an up-regulation of these miRNAs. We further observe that forced expression of this miRNA cluster increases proliferation and inhibits apoptosis of human cells. More importantly, we show that this miRNA cluster can significantly increase colony-forming capacity of normal mouse bone marrow progenitor cells alone and, particularly, in cooperation with MLL fusions. Finally, through combinatorial analysis of miRNA and mRNA arrays of mouse bone marrow progenitor cells transfected with this miRNA cluster and/or MLL fusion gene, we identified 363 potential miR-17-92 target genes that exhibited a significant inverse correlation of expression with the miRNAs. Remarkably, these potential target genes are significantly enriched (P < 0.01; >2-fold) in cell differentiation, hematopoiesis, cell cycle, and apoptosis. Taken together, our studies suggest that overexpression of miR-17-92 cluster in MLL-rearranged leukemias is likely attributed to both DNA copy number amplification and direct up-regulation by MLL fusions, and that the miRNAs in this cluster may play an essential role in the development of MLL-associated leukemias through inhibiting cell differentiation and apoptosis, while promoting cell proliferation, by regulating relevant target genes.cell apoptosis and viability | colony-forming/replating assay | MLL binding | gene regulation | miRNA target M icroRNAs (miRNAs, miRs) are endogenous ≈22 nucleotides (nt) noncoding RNAs that play important regulatory roles in animals and plants by binding with the 3′ UTRs of messenger RNAs (mRNAs) of target genes, leading to mRNA cleavage/degradation or translational repression (1-4). Rapidly accumulating evidence has revealed that miRNAs are strongly associated with cancer (3, 5-7). Recent studies suggest that a cluster of miRNAs, the miR-17-92 polycistron located at 13q31 [containing seven individual miRNAs including miR-17-5p (now named miR-17), miR-17-3p (now named miR-17*), miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-92a-1], may function as an oncogene (8-12). Particularly, He et al. (8) showed that enforced expression of the miR-17-92 cluster cooperated with Myc expression to accelerate tumor development in a mouse model of human B-cell lymphoma. Its oncogenic function is further supported by the finding that miRNAs from this cluster are overexpressed in lung, breast, colon, pancreas, prostate tumors, and chronic leukemias, and that overexpression of these miRNAs is usually correlated with the amplification of its genomic lo...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Aberrant overexpression and function of the miR-17-92 cluster in MLL -rearranged acute leukemia

Mi¹,

Li²,

Chen³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

138

125

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“…30 Therefore miR-152 can be added to the growing list of so-called 'epi-miRNAs', such as miR-29b and miR-290, which control the regulation of DNMTs. 40 MiR-148 has recently been added to this list of epigenetic effector miRNAs because it targets DNMT3b. 41 As we have shown in this study, the degree of miR-152 methylation varies among t(4;11)-positive infant ALL samples and is highly predictive for clinical outcome.…”

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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“…79 Others have added miR-290 to this list of so-called 'epi-miRNAs' upon the finding that miR-290 controlled DNA methylation and telomere recombination through retinoblastoma-like 2-dependent regulation of DNMTs. 80 Interestingly, a recent report demonstrated the discovery of a new class of miRNAs that directly (independent of target genes) mediated DNA methylation in plants. 81 After their loading into AGO4 clade proteins, these 24 nucleotide long miRNAs (lmiRNAs) directed DNA methylation at their own loci in cis as well as at their target genes in trans resulting a downregulation of target genes, likely via recruitment of de novo cytosine methyltransferase DRM2.…”

Section: Mirnas As Bystanders and Actors Of Epigeneticsmentioning

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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Leukaemogenesis: more than mutant genes

Cited by 286 publications

References 188 publications

Aberrant overexpression and function of the miR-17-92 cluster in MLL -rearranged acute leukemia

Aberrant overexpression and function of the miR-17-92 cluster in MLL -rearranged acute leukemia

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

MicroRNAs in acute leukemia: from biological players to clinical contributors

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