Portal de Periódicos da CAPES

Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome

2021; Nature Portfolio; Volume: 12; Issue: 1 Linguagem: Inglês

10.1038/s41467-021-21588-4

2041-1723

Alyssa L. Kennedy, Kasiani C. Myers, James R. Bowman, Christopher J. Gibson, Nicholas D. Camarda, Elissa Furutani, Gwen M. Muscato, Robert H. Klein, Kaitlyn Ballotti, Shanshan Liu, Chad E. Harris, Ashley Galvin, Maggie Malsch, David C. Dale, John M. Gansner, Taizo A. Nakano, Alison A. Bertuch, Adrianna Vlachos, Jeffrey M. Lipton, Paul Castillo, James A. Connelly, Jane E. Churpek, John Edwards, Nobuko Hijiya, Richard Ho, Inga Hofmann, James N. Huang, Sioḃán Keel, Adam J. Lamble, Bonnie Lau, Maxim Norkin, Elliot Stieglitz, Wendy Stock, Kelly Walkovich, Steffen Boettcher, Christian Brendel, Mark D. Fleming, Stella M. Davies, Edie Weller, Christopher D. Bahl, Scott L. Carter, Akiko Shimamura, R. Coleman Lindsley,

Acute Myeloid Leukemia Research

Abstract To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. To define the mechanistic basis of clonal hematopoiesis in SDS, we investigate somatic mutations acquired by patients with SDS followed longitudinally. Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53 . We show that germline SBDS deficiency establishes a fitness constraint that drives selection of somatic clones via two distinct mechanisms with different clinical consequences. EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness. TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect. Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations. These results mechanistically link leukemia predisposition to germline genetic constraints on cellular fitness, and provide a rational framework for clinical surveillance strategies.