Combined single nucleotide polymorphism-based genomic mapping and global gene expression profiling identifies novel chromosomal imbalances, mechanisms and candidate genes important in the pathogenesis of T-cell prolymphocytic leukemia with inv(14)(q11q32)

Dürig, Jan; Bug, Stefanie; Klein-Hitpaß, Ludger; Boes, Tanja; Jöns, Thomas; Martin-Subero, José Ignacio; Harder, Lana; Baudis, Michael; Dührsen, Ulrich; Siebert, Reiner

doi:10.1038/sj.leu.2404877

Cited by 95 publications

(88 citation statements)

References 40 publications

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“…27 In human T-cell prolymphocytic leukemia, SIX1 is found to be significantly overexpressed in comparison to normal T cells. 36 A role for these genes in carcinogenesis is also supported by previous reports which showed overexpression of both SIX1 and EYA1 in cancers of the lung, breast, prostate, cervix, and kidney (Rhodes et al 28 and supplemental Figure 9). Similarly, overexpression of HOXA9 and MEIS1 is not limited to MLLrearranged leukemias.…”

Section: Key Target Genes In Mll-rearranged Leukemiasupporting

confidence: 58%

MLL fusion proteins preferentially regulate a subset of wild-type MLL target genes in the leukemic genome

Wang

et al. 2011

Blood

104

120

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IntroductionChromosomal translocations often lead to creation of chimeric fusion genes that define cancer subtypes and act as initiating events in oncogenesis. Fusion genes can acquire novel biologic features via their fusion partners, yet retain important functions of the wild-type protein. When chromosomal rearrangements involve genes encoding DNA-binding proteins, chimeric fusion proteins can serve as aberrant transcription factors leading to genome-wide dysregulation in gene expression. Studies have shown that fusion transcription factors may gain novel specificity in target gene selection. The EWS/FLI1 oncogenic transcription factor modulates a specific set of genes that are not bound by wild-type FLI1 in vivo. 1 The AML1-ETO fusion protein preferentially binds to duplicated AML-1 DNA-binding sequences. 2 In acute promyelocytic leukemia (APL), the PML/RAR␣ fusion protein is selectively targeted to regions containing PU.1 consensus and RARE (retinoic acid response elements) half sites. The majority of those sites do not correspond to canonical RAREs. 3 Chromosomal translocations involving the MLL (mixed-lineage leukemia) gene result in the formation of a chimeric transcription factor. It remains unknown whether the MLL fusion protein shares the same set of target genes compared with the wild-type MLL protein.The histone methyltransferase MLL gene is frequently targeted by chromosomal translocations in acute myeloid, lymphoid, and biphenotypic leukemias, and rearrangement of MLL is associated with a poor prognosis. Wild-type MLL is critical for the maintenance of expression of its target genes. This activity is mediated by its carboxyl-terminal SET domain, which acts as a histone 3 lysine-4 (H3K4) methyltransferase. 4,5 The critical consequence of 11q23 chromosomal translocations is the formation of a chimeric oncogenic transcription factor that retains the N-terminus of MLL but replaces carboxyl-terminal domains with sequences from its partner proteins. As a result of 11q23 gene rearrangements, MLL fuses in frame with Ͼ 60 different partner proteins. 6 The most common partners are AF4, AF9, ENL, AF10, and ELL, which together account for Ͼ 85% of all MLL-rearranged leukemias. AF4, ENL, AF9, and AF10 form a complex that promotes H3K79 methylation through recruitment of histone methyltransferase DOT1L. 7,8 Aberrant H3K79 methylation has been shown to be a key molecular mechanism in MLL fusion-induced dysregulation of gene expression. 9,10 MLL is targeted to a specific set of gene loci, presumably via its own DNA binding domain, recognition of local histone modifications, and/or recruitment by sequence-specific transcription factors. 11 However, the target genes of MLL fusion proteins compared with wild-type MLL remain poorly understood. In MLL-AF4-expressing mouse acute lymphoid leukemia cells, thousands of gene promoters exhibited increased levels of H3K79 methylation in comparison to normal control lymphocytes, suggesting MLL-AF4 has widespread targets in the leukemic genome. 12 In contrast, by looking for co...

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Section: Key Target Genes In Mll-rearranged Leukemiasupporting

confidence: 58%

MLL fusion proteins preferentially regulate a subset of wild-type MLL target genes in the leukemic genome

Wang

et al. 2011

Blood

104

120

View full text Add to dashboard Cite

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“…Overexpression of STEAP1 was also found in primary effusion lymphoma compared to normal B cells (P = 3.1E-5) [31] and in various leukemia compared to normal bone marrow: T-cell acute lymphoblastic leukemia (P = 5.6E-9) [32], acute myeloid leukemia (P = 5.6E-9) [32]; B-cell acute lymphoblastic leukemia (P = 8.3E-12) [32]; and T-cell prolymphocytic leukemia (P = 5.1E-7) [33].…”

Section: Resultsmentioning

confidence: 98%

STEAP1 is overexpressed in cancers: A promising therapeutic target

Moreaux

Kassambara

Hose

et al. 2012

Biochemical and Biophysical Research Communications

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The six-transmembrane epithelial antigen of prostate (STEAP) protein was identified in advanced prostate cancer and is up-regulated in multiple cancer cell lines, including prostate, bladder, colon, ovarian, and Ewing sarcoma. STEAP1 was described as a suitable antigen for T-cell-based or antibody-based immunotherapy.We have investigated the expression of STEAP1 in 40 human tumor types -brain, epithelial, lymphoid -and in their normal tissue counterparts using publicly available gene expression data, including the Oncomine Cancer Microarray database. STEAP1 was found significantly overexpressed in 11 cancers. In addition, high STEAP1 expression was associated with poor overall survival in colorectal cancer, diffuse large B cell lymphoma, acute myeloid leukemia and multiple myeloma.Taken together, these data suggest that STEAP1 is a potential therapeutic target for Tcell based immunotherapy or antibody therapy in a large panel of cancers.3

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“…This approach of combining copy number and gene expression data has been successful in other indications (7,9,11,35); the impact of copy number on gene expression pattern shows generally more dramatic effects in the case of high-level copy number increase, whereas low-level copy number gains and losses, although have significant influence on expression of genes in the regions affected, display more subtle effects on a gene-by-gene basis (24,36). Therefore, we applied stringent parameters of statistical significance to identify genes whose differential expression is more likely to be attributable to underlying low-level gene copy number changes; this led to the identification of 113 genes differentially expressed in regions of genomic gain and loss.…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Regions and Genes Important in the Pathogenesis of Sézary Syndrome by Combining Genomic and Expression Microarrays

et al. 2009

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In this study, we used single nucleotide polymorphism and comparative genomic hybridization array to study DNA copy number changes and loss of heterozygosity for 28 patients affected by Sézary syndrome (SS), a rare form of cutaneous Tcell lymphoma (CTCL). Our data identified, further confirming previous studies, recurrent losses of 17p13.2-p11.2 and 10p12.1-q26.3 occurring in 71% and 68% of cases, respectively; common gains were detected for 17p11.2-q25.3 (64%) and chromosome 8/8q (50%). Moreover, we identified novel genomic lesions recurring in >30% of tumors: loss of 9q13-q21.33 and gain of 10p15.3-10p12.2. Individual chromosomal aberrations did not show a significant correlation with prognosis; however, when more than three recurrent chromosomal alterations (gain or loss) were considered, a statistical association was observed using Kaplan-Meier survival analysis. Integrating mapping and transcriptional data, we were able to identify a total of 113 deregulated transcripts in aberrant chromosomal regions that included cancer-related genes such as members of the NF-κB pathway (BAG4, BTRC, NKIRAS2, PSMD3, and TRAF2) that might explain its constitutive activation in CTCL. Matching this list of genes with those discriminating patients with different survival times, we identify several common candidates that might exert critical roles in SS, such as BUB3 and PIP5K1B. Altogether, our study confirms and maps more precisely the regions of gain and loss and, combined to transcriptional profiles, suggests a novel set of genes of potential interest in SS. [Cancer Res 2009;69(21):8438-46]

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Combined single nucleotide polymorphism-based genomic mapping and global gene expression profiling identifies novel chromosomal imbalances, mechanisms and candidate genes important in the pathogenesis of T-cell prolymphocytic leukemia with inv(14)(q11q32)

Cited by 95 publications

References 40 publications

MLL fusion proteins preferentially regulate a subset of wild-type MLL target genes in the leukemic genome

MLL fusion proteins preferentially regulate a subset of wild-type MLL target genes in the leukemic genome

STEAP1 is overexpressed in cancers: A promising therapeutic target

Identification of Key Regions and Genes Important in the Pathogenesis of Sézary Syndrome by Combining Genomic and Expression Microarrays

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