| Autor: |
Maxim Norkin, Sixi Liu, R. C. Lindsley, Alison A. Bertuch, Christopher D. Bahl, Ashley Galvin, Jane E. Churpek, Nicholas D. Camarda, Elissa Furutani, Wendy Stock, Jeffrey M. Lipton, Bonnie W Lau, Christian Brendel, James A. Connelly, Scott L. Carter, Steffen Boettcher, David C. Dale, Sioban Keel, Alyssa L. Kennedy, Kasiani C. Myers, Inga Hofmann, John R. Edwards, Akiko Shimamura, James Bowman, Chad E. Harris, James N. Huang, Richard H. Ho, Rüdiger Klein, Mark D. Fleming, Maggie Malsch, Taizo A. Nakano, Adrianna Vlachos, John M. Gansner, Christopher J. Gibson, Stella M. Davies, Elliot Stieglitz, Paul Castillo, Adam J. Lamble, Edie Weller, G. M. Muscato, Nobuko Hijiya, Kaitlyn Ballotti, Kelly Walkovich |
| Rok vydání: |
2020 |
| Předmět: |
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| Popis: |
Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome with predisposition to developing leukemia. We found that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations inEIF6orTP53.EIF6mutations cause functional compensation for the germline deficiency by alleviating the SDS ribosome joining defect, improving translation, and reducing p53 activation.TP53mutations decrease checkpoint activation without affecting ribosome assembly. We link development of leukemia with acquisition of biallelicTP53alterations. Our results define distinct pathways of clonal selection driven by germline fitness constraint and provide a mechanistic framework for clinical surveillance. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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