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.