Thank you! Your submission has been received!
Oops! Something went wrong while submitting the form.
X
Announcing the new Tapestri Solution for Solid Tumor Oncology Research. Learn More
X
publication

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


Kennedy, A.L. et al.
Nature Communications (2021)
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.



Authors

Kennedy, A.L., Myers K.C., Bowman, J., Gibson, C.J., Camarda, N.D., Furutani, E., Muscato, G.M., Klein, R.H., Ballotti, K., Liu, S., Harris, C.E., Galvin, A., Malsch, M., Dale, D., Gansner, J.M., Nakano, T.A., Bertuch, A., Vlachos, A., Lipton, J.M., Castillo, P., Connelly, J., Churpek, J., Edwards, J.R., Hijiya, N., Ho, R.H., Hofmann, I., Huang, J.N., Keel, S., Lamble, A., Lau, B.W., Norkin, M., Stieglitz, E., Stock, W., Walkovich, K., Boettcher, S., Brendel, C.,Fleming, M.D., Davies, S.M., Weller, E.A., Bahl, C., Carter, S.L., Shimamura, A., Lindsley, R.C.



VIEW

publication
Single cell genotypic and phenotypic analysis of measurable residual disease in acute myeloid leukemia
Troy T. Robinson
publication
The genomic landscape of pediatric acute lymphoblastic leukemia
Samuel W. Brady
Nature Genetics
publication
Detection of early seeding of Richter transformation in chronic lymphocytic leukemia
Ferran Nadeu
Nature Medicine (2022)
publication
Modeling clonal evolution and oncogenic dependency in vivo in the context of hematopoietic transformation
Bowman RL
BioRxiv (2022)
REQUEST QUOTE