Mice heterozygous for CREB binding protein are hypersensitive to γ-radiation and invariably develop myelodysplastic/myeloproliferative neoplasm

摘要: Myelodysplastic syndrome is a complex family of preleukemic diseases in which hematopoietic stem cell defects lead to abnormal differentiation one or more blood lineages. Disease progression associated with increasing genomic instability and large proportion patients go on develop acute myeloid leukemia. Primarily disease the elderly, it can also after chemotherapy. We have previously reported that CREB binding protein ( Crebbp) heterozygous mice an increased incidence hematological malignancies, others shown CREBBP genes altered by chromosomal translocations found suffering from therapy-related myelodysplastic syndrome. This led us investigate whether tumor development Crebbp +/− preceded phase we could uncover molecular mechanisms might contribute its development. report here invariably myelodysplastic/myeloproliferative neoplasm within 9 12 months age. They are hypersensitive ionizing radiation show marked decrease poly(ADP-ribose) polymerase-1 activity irradiation. In addition, levels XRCC1 APEX1, key components base excision repair machinery, reduced unirradiated cells upon targeted knockdown levels. Our results provide validation novel mouse model and, importantly, point defective DNA damage as contributing factor pathogenesis this currently incurable disease.