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

Alyssa L. Kennedy, Kasiani C. Myers, James 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 Dale, John M. Gansner, Taizo A. Nakano, Alison Bertuch, Adrianna Vlachos, Jeffrey M. Lipton, Paul Castillo, James Connelly, Jane Churpek, John R. Edwards, Nobuko Hijiya, Richard H. Ho, Inga Hofmann, James N. Huang, Siobán Keel, Adam Lamble, Bonnie W. Lau, Maxim Norkin, Elliot Stieglitz, Wendy Stock, Kelly Walkovich, Steffen Boettcher, Christian Brendel, Mark D. Fleming, Stella M. Davies, Edie A. Weller, Christopher Bahl, Scott L. Carter, Akiko Shimamura and R. Coleman Lindsley ()
Additional contact information
Alyssa L. Kennedy: Harvard Medical School
Kasiani C. Myers: University of Cincinnati College of Medicine
James Bowman: Harvard Medical School
Christopher J. Gibson: Division of Hematological Malignancies Dana-Farber Cancer Institute
Nicholas D. Camarda: Dana-Farber Cancer Institute
Elissa Furutani: Harvard Medical School
Gwen M. Muscato: Boston Children’s Hospital
Robert H. Klein: Dana-Farber Cancer Institute
Kaitlyn Ballotti: Boston Children’s Hospital
Shanshan Liu: Boston Children’s Hospital
Chad E. Harris: Boston Children’s Hospital
Ashley Galvin: Boston Children’s Hospital
Maggie Malsch: Boston Children’s Hospital
David Dale: University of Washington
John M. Gansner: Brigham and Women’s Hospital
Taizo A. Nakano: University of Colorado School of Medicine
Alison Bertuch: Baylor College of Medicine
Adrianna Vlachos: Cohen Children’s Medical Center of New York
Jeffrey M. Lipton: Cohen Children’s Medical Center of New York
Paul Castillo: University of Florida
James Connelly: Vanderbilt University Medical Center
Jane Churpek: The University of Wisconsin-Madison
John R. Edwards: Indiana Blood and Marrow Transplantation
Nobuko Hijiya: Columbia University Medical Center
Richard H. Ho: Vanderbilt University Medical Center
Inga Hofmann: University of Wisconsin
James N. Huang: UCSF Benioff Children’s Hospital
Siobán Keel: University of Washington
Adam Lamble: Seattle Children’s Hospital
Bonnie W. Lau: Geisel School of Medicine
Maxim Norkin: Baptist MD Anderson Cancer Center
Elliot Stieglitz: UCSF Benioff Children’s Hospital
Wendy Stock: University of Chicago
Kelly Walkovich: University of Michigan Medical School
Steffen Boettcher: University Hospital Zurich and University of Zurich
Christian Brendel: Harvard Medical School
Mark D. Fleming: Boston Children’s Hospital
Stella M. Davies: University of Cincinnati College of Medicine
Edie A. Weller: Harvard Medical School
Christopher Bahl: Harvard Medical School
Scott L. Carter: Broad Institute
Akiko Shimamura: Harvard Medical School
R. Coleman Lindsley: Division of Hematological Malignancies Dana-Farber Cancer Institute

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-021-21588-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21588-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-21588-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().