Fusion of AML1/Runx1 to Copine VIII, a novel member of the copine family, in an aggressive acute myelogenous leukemia with t(12;21) translocation

Ramsey, H. E.; Zhang, Do.-E.; Richkind, Kathleen E.; Burcoglu-O'ral, A.; Hromas, Robert

doi:10.1038/sj.leu.2403048

Cited by 35 publications

(30 citation statements)

References 8 publications

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“…These large hypomethylated regions are also AT-rich, low in CPGI, and show low sequence conservation with other genomes. Several extensively hypomethylated large genes have also been shown to reside at the chromosomal breakpoints of chromosomal rearrangement/deletion, such as PRDM16 (Stevens-Kroef et al 2006), AKT3 (Boland et al 2007), MDS1 (Cherry et al 2001), PTPRZ1 (Mulholland et al 2006), CPNE8 (Ramsey et al 2003), NKAIN2 (Bocciardi et al 2005), NTRK3 (Jin et al 2007), and NRG1 (Adelaide et al 2000). These results support the hypothesis that hypomethylation is involved in genome instability (Dodge et al 2005) through recombination of unmethylated sequences.…”

Section: Discussionsupporting

confidence: 78%

Genome-wide mapping and characterization of hypomethylated sites in human tissues and breast cancer cell lines

Shann¹,

Cheng²,

Chiao³

et al. 2008

Genome Res.

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We have developed a method for mapping unmethylated sites in the human genome based on the resistance of TspRI-digested ends to ExoIII nuclease degradation. Digestion with TspRI and methylation-sensitive restriction endonuclease HpaII, followed by ExoIII and single-strand DNA nuclease allowed removal of DNA fragments containing unmethylated HpaII sites. We then used array comparative genomic hybridization (CGH) to map the sequences depleted by these procedures in human genomes derived from five human tissues, a primary breast tumor, and two breast tumor cell lines. Analysis of methylation patterns of the normal tissue genomes indicates that the hypomethylated sites are enriched in the 5Ј end of widely expressed genes, including promoter, first exon, and first intron. In contrast, genomes of the MCF-7 and MDA-MB-231 cell lines show extensive hypomethylation in the intragenic and intergenic regions whereas the primary tumor exhibits a pattern between those of the normal tissue and the cell lines. A striking characteristic of tumor cell lines is the presence of megabase-sized hypomethylated zones. These hypomethylated zones are associated with large genes, fragile sites, evolutionary breakpoints, chromosomal rearrangement breakpoints, tumor suppressor genes, and with regions containing tissue-specific gene clusters or with gene-poor regions containing novel tissue-specific genes. Correlation with microarray analysis shows that genes with a hypomethylated sequence 2 kb up-or downstream of the transcription start site are highly expressed, whereas genes with extensive intragenic and 3Ј untranslated region (UTR) hypomethylation are silenced. The method described herein can be used for large-scale screening of changes in the methylation pattern in the genome of interest.

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Section: Discussionsupporting

confidence: 78%

Genome-wide mapping and characterization of hypomethylated sites in human tissues and breast cancer cell lines

Shann¹,

Cheng²,

Chiao³

et al. 2008

Genome Res.

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“…31; 7x enriched) belongs to a family of closely related, predominantly cytosolic proteins equipped with two C2 domains that enable them to bind to membrane phospholipids in a Ca 2+ -dependent fashion, and one integrin-like protein-binding domain that can mediate the membrane anchorage of other proteins, including ubiquitin-conjugating enzymes and cytoskeletal proteins. [228][229][230] Copines have been implicated in signal transduction, 231 growth stimulation, cell survival 232 and cancer, 233 and one family member (copine III) has been found to possess protein kinase activity. 234 Copines have been shown to associate transiently with the plasma membrane as well as with the membranes of intracellular vacuoles, including phagosomes and lysosomes.…”

Section: Autophagosomal Membrane Proteinsmentioning

confidence: 99%

Proteomic Analysis of Membrane-Associated Proteins from Rat Liver Autophagosomes

Øverbye¹,

Fengsrud²,

Seglen³

2007

Autophagy

138

117

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“…1,2 AML1 is also the major gene involved in chromosomal translocations in leukemia, 3,4 seen translocated in both lymphoid and myeloid leukemia, such as t(8;21) (AML1-ETO), 5 t(3;21) (AML1-Evi1), 6 t(12;21) (TEL-AML1), 7 t(16;21) (AML1-MTG16), 8 t(12;21) (AML1-copine VIII), 9 t(X;21) (AML1-Fog2), 10 and t(7;21) (AML1-USP42). 11 Specifically the AML1-ETO-associated translocation is observed in approximately 40% of cases of acute myeloid leukemia of the M2 classification (AML-M2), while present in approximately 12% of AMLs.…”

Section: Introductionmentioning

confidence: 99%

The p21Waf1 pathway is involved in blocking leukemogenesis by the t(8;21) fusion protein AML1-ETO

Peterson

Yan

Zhang

2007

Blood

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The 8;21 translocation is a major contributor to acute myeloid leukemia (AML) of the M2 classification occurring in approximately 40% of these cases. Multiple mouse models using this fusion protein demonstrate that AML1-ETO requires secondary mutagenic events to promote leukemogenesis. Here, we show that the negative cell cycle regulator p21 WAF1 gene is up-regulated by AML1-ETO at the protein, RNA, and promoter levels. Retroviral transduction and hematopoietic cell transplantation experiments with p21 WAF1 -deficient cells show that AML1-ETO is able to promote leukemogenesis in the absence of p21 WAF1 . Thus, loss of p21 WAF1 facilitates AML1-ETO-induced leukemogenesis, suggesting that mutagenic events in the p21 WAF1 pathway to bypass the growth inhibitory effect from AML1-ETO-induced p21 WAF1 expression can be a significant factor in AML1-ETO-associated acute myeloid leukemia. (RUNX1) is a member of the Runt family of transcription factors that heterodimerize with CBF␤ to form a stable DNAbinding complex. 1,2 AML1 is also the major gene involved in chromosomal translocations in leukemia, 3,4 seen translocated in both lymphoid and myeloid leukemia, such as t(8;21) (AML1-ETO), 5 t(3;21) (AML1-Evi1), 6 t(12;21) (TEL-AML1), 7 t(16;21) (AML1-MTG16), 8 t(12;21) (AML1-copine VIII), 9 t(X;21) (AML1-Fog2), 10 and t(7;21) (AML1-USP42). 11 Specifically the AML1-ETO-associated translocation is observed in approximately 40% of cases of acute myeloid leukemia of the M2 classification (AML-M2), while present in approximately 12% of AMLs. This translocation protein contains the N-terminal portion of AML1 up to its Runt homology DNA-binding domain fused to most of the ETO (MTG8) protein. 12 The ETO gene is one of the family of ETO/MTG repressor proteins that have homology to the Drosophila Nervy repressor proteins. 13,14 Nonconditional AML1-ETO knock-in mice 15,16 are similar to AML1-deficient mice 17,18 in embryonic lethality and in displaying a block in embryonic definitive hematopoiesis, suggestive of a dominant-negative function. Furthermore, directed controlled expression of AML1-ETO in mice demonstrated that AML1-ETO does not promote leukemia under these circumstances. [19][20][21][22] However, following the treatment of AML1-ETO-expressing mice with a DNA-alkylating agent, the mice developed AML. 20,21 Furthermore, various retroviral transduction models have shown again that it does not promote AML. 23,24 These studies suggest that AML1-ETO requires secondary mutagenic events to promote development of AML. Indeed, AML1-ETO promotes AML when combined with the loss of the ICSBP gene, overexpression of WT1, the Flt3-activating mutation, or cotransduction with another translocation fusion protein TEL-PDGFR. [24][25][26][27] The biologic characterization of AML1-ETO in various cell lines has shown that it has both positive and negative effects on leukemia development. Its positive influence comes from its ability to block differentiation and to expand hematopoietic stem cells 23,24,[28][29][30][31][32] ; however, its negat...

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Fusion of AML1/Runx1 to Copine VIII, a novel member of the copine family, in an aggressive acute myelogenous leukemia with t(12;21) translocation

Cited by 35 publications

References 8 publications

Genome-wide mapping and characterization of hypomethylated sites in human tissues and breast cancer cell lines

Genome-wide mapping and characterization of hypomethylated sites in human tissues and breast cancer cell lines

Proteomic Analysis of Membrane-Associated Proteins from Rat Liver Autophagosomes

The p21Waf1 pathway is involved in blocking leukemogenesis by the t(8;21) fusion protein AML1-ETO

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