Author
Jane E. Churpek
Bio: Jane E. Churpek is an academic researcher from University of Wisconsin-Madison. The author has contributed to research in topics: Germline & Leukemia. The author has an hindex of 3, co-authored 6 publications receiving 25 citations.
Topics: Germline, Leukemia, Ribosomopathy, Ribosome assembly, Mutation
Papers
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Boston Children's Hospital1, Harvard University2, University of Cincinnati Academic Health Center3, Cincinnati Children's Hospital Medical Center4, Broad Institute5, University of Washington6, Brigham and Women's Hospital7, University of Colorado Denver8, Baylor College of Medicine9, Hofstra University10, University of Florida11, Vanderbilt University Medical Center12, University of Wisconsin-Madison13, Columbia University Medical Center14, Seattle Children's15, Dartmouth–Hitchcock Medical Center16, University of Texas MD Anderson Cancer Center17, University of California, San Francisco18, University of Chicago19, University of Michigan20, University of Zurich21
TL;DR: In this paper, the authors studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age.
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.
67 citations
University of Chicago1, University of Wisconsin-Madison2, University of Washington3, University of Helsinki4, University of Düsseldorf5, Hannover Medical School6, Northwestern University7, University of Calgary8, Albert Einstein College of Medicine9, Roswell Park Cancer Institute10, Houston Methodist Hospital11
30 citations
18 citations
Boston Children's Hospital1, Harvard University2, Cincinnati Children's Hospital Medical Center3, University of Cincinnati Academic Health Center4, Broad Institute5, University of Washington6, Brigham and Women's Hospital7, University of Colorado Denver8, Baylor College of Medicine9, Hofstra University10, University of Florida11, Vanderbilt University Medical Center12, University of Wisconsin-Madison13, Columbia University Medical Center14, Seattle Children's15, Dartmouth–Hitchcock Medical Center16, University of Texas MD Anderson Cancer Center17, University of California, San Francisco18, University of Chicago19, University of Michigan20, University of Zurich21
TL;DR: It is found that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53.
Abstract: 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 in EIF6 or TP53. EIF6 mutations cause functional compensation for the germline deficiency by alleviating the SDS ribosome joining defect, improving translation, and reducing p53 activation. TP53 mutations decrease checkpoint activation without affecting ribosome assembly. We link development of leukemia with acquisition of biallelic TP53 alterations. Our results define distinct pathways of clonal selection driven by germline fitness constraint and provide a mechanistic framework for clinical surveillance.
6 citations
01 Sep 2020
1 citations
Cited by
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TL;DR: The authors, a group with expertise in the clinical, pathologic and genetic aspects of these disorders, developed the International Consensus Classification (ICC), aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.
444 citations
TL;DR: The genetic and clinical spectrum of predisposition to MN is described, with the main focus lies in delineation of phenotypes, genetics and management of GATA2 deficiency and the novel SAMD9/SAMD9L-related disorders.
49 citations
TL;DR: There is evidence that genotoxic stress from chemotherapy or radiation therapy, ribosome biogenesis stress, and possibly inflammation may increase the risk of transformation from clonal hematopoiesis to a myeloid malignancy.
44 citations
TL;DR: A framework by which an understanding of the processes that promote clonal hematopoiesis in IBMFS may inform clinical surveillance strategies is described.
34 citations
TL;DR: This report aims to help physicians and laboratorians implement genomic testing for diagnosis, risk stratification, and clinical decision making and illustrates the potential of genomic profiling for enabling personalized medicine in patients with these hematologic neoplasms.
31 citations