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3 results on '"Kristina Owens"'

1. Global Identification of EVI1 Target Genes in Acute Myeloid Leukemia.

Author

Carolyn Glass, Charles Wuertzer, Xiaohui Cui, Yingtao Bi, Ramana Davuluri, Ying-Yi Xiao, Michael Wilson, Kristina Owens, Yi Zhang, and Archibald Perkins

Subjects
Medicine, Science
Abstract

The ecotropic virus integration site 1 (EVI1) transcription factor is associated with human myeloid malignancy of poor prognosis and is overexpressed in 8-10% of adult AML and strikingly up to 27% of pediatric MLL-rearranged leukemias. For the first time, we report comprehensive genomewide EVI1 binding and whole transcriptome gene deregulation in leukemic cells using a combination of ChIP-Seq and RNA-Seq expression profiling. We found disruption of terminal myeloid differentiation and cell cycle regulation to be prominent in EVI-induced leukemogenesis. Specifically, we identified EVI1 directly binds to and downregulates the master myeloid differentiation gene Cebpe and several of its downstream gene targets critical for terminal myeloid differentiation. We also found EVI1 binds to and downregulates Serpinb2 as well as numerous genes involved in the Jak-Stat signaling pathway. Finally, we identified decreased expression of several ATP-dependent P2X purinoreceptors genes involved in apoptosis mechanisms. These findings provide a foundation for future study of potential therapeutic gene targets for EVI1-induced leukemia.

Published
2013
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2. Essential role of PR-domain protein MDS1-EVI1 in MLL-AF9 leukemia

Author

Carolyn Glass, Kannan Karuppaiah, Yi Zhang, Kristina Owens, Fernando D. Camargo, Layla Hatem, and Archibald S. Perkins

Subjects
Gene isoform, Histone methyltransferase activity, Oncogene Proteins, MECOM, Oncogene Proteins, Fusion, Immunology, Protein domain, Biology, Biochemistry, Leukemogenic, Mice, Bone Marrow, hemic and lymphatic diseases, medicine, Animals, Humans, Protein Isoforms, Cell Lineage, neoplasms, Alleles, Mice, Knockout, Myeloid Neoplasia, Gene Expression Regulation, Leukemic, Cell Biology, Hematology, Exons, medicine.disease, Molecular biology, Fusion protein, Cell biology, Leukemia, Biphenotypic, Acute, Leukemia, Cell Transformation, Neoplastic, Phenotype, Myeloid-Lymphoid Leukemia Protein
Abstract

A subgroup of leukemogenic mixed-lineage leukemia (MLL) fusion proteins (MFPs) including MLL-AF9 activates the Mecom locus and exhibits extremely poor clinical prognosis. Mecom encodes EVI1 and MDS1-EVI1 (ME) proteins via alternative transcription start sites; these differ by the presence of a PRDI-BF1-RIZ1 (PR) domain with histone methyltransferase activity in the ME isoform. Using an ME-deficient mouse, we show that ME is required for MLL-AF9-induced transformation both in vitro and in vivo. And, although Nup98-HOXA9, MEIS1-HOXA9, and E2A-Hlf could transform ME-deficient cells, both MLL-AF9 and MLL-ENL were ineffective, indicating that the ME requirement is specific to MLL fusion leukemia. Further, we show that the PR domain is essential for MFP-induced transformation. These studies clearly indicate an essential role of PR-domain protein ME in MFP leukemia, suggesting that ME may be a novel target for therapeutic intervention for this group of leukemias.

Published
2013

3. Global Identification of EVI1 Target Genes in Acute Myeloid Leukemia

Author

Archibald S. Perkins, Xiaohui Cui, Ramana V. Davuluri, Ying Yi Xiao, Yingtao Bi, Michael P Wilson, Yi Zhang, Charles A. Wuertzer, Kristina Owens, and Carolyn Glass

Subjects
Myeloid, Cellular differentiation, Gene Identification and Analysis, Hematologic Cancers and Related Disorders, Mice, 0302 clinical medicine, hemic and lymphatic diseases, Genetics, Regulation of gene expression, 0303 health sciences, Multidisciplinary, Myeloid leukemia, Cell Differentiation, Hematology, 3. Good health, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Leukemia, Leukemia, Myeloid, Acute, medicine.anatomical_structure, STAT1 Transcription Factor, 030220 oncology & carcinogenesis, Medicine, Sequence Analysis, Signal Transduction, Research Article, Acute Myeloid Leukemia, Science, Biology, Cell Line, Molecular Genetics, 03 medical and health sciences, Proto-Oncogenes, Leukemias, medicine, Plasminogen Activator Inhibitor 2, Animals, Humans, 030304 developmental biology, Janus Kinases, RUNX1T1, Computational Biology, CEBPE, medicine.disease, MDS1 and EVI1 Complex Locus Protein, Gene expression profiling, Cancer research, CCAAT-Enhancer-Binding Proteins, Transcriptome, Transcription Factors, Developmental Biology
Abstract

The ecotropic virus integration site 1 (EVI1) transcription factor is associated with human myeloid malignancy of poor prognosis and is overexpressed in 8-10% of adult AML and strikingly up to 27% of pediatric MLL-rearranged leukemias. For the first time, we report comprehensive genomewide EVI1 binding and whole transcriptome gene deregulation in leukemic cells using a combination of ChIP-Seq and RNA-Seq expression profiling. We found disruption of terminal myeloid differentiation and cell cycle regulation to be prominent in EVI-induced leukemogenesis. Specifically, we identified EVI1 directly binds to and downregulates the master myeloid differentiation gene Cebpe and several of its downstream gene targets critical for terminal myeloid differentiation. We also found EVI1 binds to and downregulates Serpinb2 as well as numerous genes involved in the Jak-Stat signaling pathway. Finally, we identified decreased expression of several ATP-dependent P2X purinoreceptors genes involved in apoptosis mechanisms. These findings provide a foundation for future study of potential therapeutic gene targets for EVI1-induced leukemia.

Published
2012

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