Mice heterozygous for CREB binding protein are hypersensitive to γ-radiation and invariably develop myelodysplastic/myeloproliferative neoplasm
| Autor: | Claudia Day, Qing Zhou, Stephanie N. Zimmer, Vivienne I. Rebel, Madeleine E. Lemieux, Bijal Karia, Yi Chen, Uthra Suresh, Ting Zhou, Alexander J.R. Bishop, Andrew L. Kung, Marsha C. Kinney |
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| Rok vydání: | 2011 |
| Předmět: |
Genome instability
Cancer Research Heterozygote DNA Repair Radiation Tolerance Genomic Instability Article XRCC1 Mice Myeloproliferative Disorders Genetics medicine Animals Preleukemia Gene Regulatory Networks CREB-binding protein RNA Small Interfering Molecular Biology Myeloproliferative neoplasm biology Myelodysplastic syndromes Myelodysplastic/Myeloproliferative Neoplasm Myeloid leukemia Cell Biology Hematology medicine.disease CREB-Binding Protein Mice Inbred C57BL Gene Expression Regulation Gamma Rays Gene Knockdown Techniques Myelodysplastic Syndromes Immunology Cancer research biology.protein Disease Progression Whole-Body Irradiation DNA Damage |
| Zdroj: | Experimental hematology. 40(4) |
| ISSN: | 1873-2399 |
| Popis: | Myelodysplastic syndrome is a complex family of preleukemic diseases in which hematopoietic stem cell defects lead to abnormal differentiation in one or more blood lineages. Disease progression is associated with increasing genomic instability and a large proportion of patients go on to develop acute myeloid leukemia. Primarily a disease of the elderly, it can also develop after chemotherapy. We have previously reported that CREB binding protein ( Crebbp) heterozygous mice have an increased incidence of hematological malignancies, and others have shown that CREBBP is one of the genes altered by chromosomal translocations found in patients suffering from therapy-related myelodysplastic syndrome. This led us to investigate whether hematopoietic tumor development in Crebbp +/− mice is preceded by a myelodysplastic phase and whether we could uncover molecular mechanisms that might contribute to its development. We report here that Crebbp +/− mice invariably develop myelodysplastic/myeloproliferative neoplasm within 9 to 12 months of age. They are also hypersensitive to ionizing radiation and show a marked decrease in poly(ADP-ribose) polymerase-1 activity after irradiation. In addition, protein levels of XRCC1 and APEX1, key components of base excision repair machinery, are reduced in unirradiated Crebbp +/− cells or upon targeted knockdown of CREBBP levels. Our results provide validation of a novel myelodysplastic/myeloproliferative neoplasm mouse model and, more importantly, point to defective repair of DNA damage as a contributing factor to the pathogenesis of this currently incurable disease. |
| Databáze: | OpenAIRE |
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