title: Chromosome instability underlies hematopoietic stem cell dysfunction and lymphoid neoplasia associated with impaired Fbw7-mediated cyclin E regulation.
abstract: The Fbw7 ubiquitin ligase critically regulates hematopoietic stem cell (HSC) function, though the precise contribution of individual substrate ubiquitination pathways to HSC homeostasis is unknown. In the work reported here, we used a mouse model in which we introduced two knock-in mutations (T74A and T393A [changes of T to A at positions 74 and 393]) to disrupt Fbw7-dependent regulation of cyclin E, its prototypic substrate, and to examine the consequences of cyclin E dysregulation for HSC function. Serial transplantation revealed that cyclin E(T74A T393A) HSCs self-renewed normally; however, we identified defects in their multilineage reconstituting capacity. By inducing hematologic stress, we exposed an impaired self-renewal phenotype in cyclin E knock-in HSCs that was associated with defective cell cycle exit and the emergence of chromosome instability (CIN). Importantly, p53 deletion induced both defects in self-renewal and multilineage reconstitution in cyclin E knock-in HSCs with serial transplantation and CIN in hematopoietic stem and progenitor cells. Moreover, CIN was a feature of fatal T-cell malignancies that ultimately developed in recipients of cyclin E(T74A T393A); p53-null HSCs. Together, our findings demonstrate the importance of Fbw7-dependent cyclin E control to the hematopoietic system and highlight CIN as a characteristic feature of HSC dysfunction and malignancy induced by deregulated cyclin E.
authors: Department of Medicine, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA Driskill Graduate Program in Life Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors: Ka Tat
authors: KT
authors: Siu
authors: Department of Medicine, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors: Yanfei
authors: Y
authors: Xu
authors: Department of Medicine, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA Driskill Graduate Program in Life Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors: Kelsey L
authors: KL
authors: Swartz
authors: Department of Medicine, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors: Mitra
authors: M
authors: Bhattacharyya
authors: Section of Hematopathology, Department of Pathology, University of Chicago Medical Center, Chicago, Illinois, USA.
authors: Sandeep
authors: S
authors: Gurbuxani
authors: Department of Medicine, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors: Youjia
authors: Y
authors: Hua
authors: Department of Medicine, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA a-minella@northwestern.edu.
authors: Alex C
authors: AC
authors: Minella
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D019070:Cell Lineage; D043171:Chromosomal Instability / Q000235:genetics / Q000502:physiology*; D019927:Cyclin E / Q000235:genetics* / Q000378:metabolism*; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D016158:Genes, p53; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000473:pathology / Q000502:physiology*; D016399:Lymphoma, T-Cell / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism*
chemical_list: D019927:Cyclin E; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513272:Fbxw7 protein, mouse; D050505:Mutant Proteins; D011994:Recombinant Proteins; D044767:Ubiquitin-Protein Ligases