title: Mice heterozygous for CREB binding protein are hypersensitive to γ-radiation and invariably develop myelodysplastic/myeloproliferative neoplasm.
abstract: 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.
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, TX 78229, USA.
authors.forename: Stephanie N
authors.initials: SN
authors.lastname: Zimmer
authors.forename: Madeleine E
authors.initials: ME
authors.lastname: Lemieux
authors.forename: Bijal P
authors.initials: BP
authors.lastname: Karia
authors.forename: Claudia
authors.initials: C
authors.lastname: Day
authors.forename: Ting
authors.initials: T
authors.lastname: Zhou
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: Uthra
authors.initials: U
authors.lastname: Suresh
authors.forename: Yidong
authors.initials: Y
authors.lastname: Chen
authors.forename: Marsha C
authors.initials: MC
authors.lastname: Kinney
authors.forename: Alexander J R
authors.initials: AJ
authors.lastname: Bishop
authors.forename: Vivienne I
authors.initials: VI
authors.lastname: Rebel
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein / Q000235:genetics* / Q000502:physiology; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D018450:Disease Progression; D005720:Gamma Rays / Q000009:adverse effects*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D042822:Genomic Instability; D006579:Heterozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D009196:Myeloproliferative Disorders / Q000235:genetics*; D011289:Preleukemia / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000633:toxicity; D011836:Radiation Tolerance / Q000235:genetics*; D014916:Whole-Body Irradiation / Q000009:adverse effects
chemical_list: D034741:RNA, Small Interfering; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse