In this issue: New research contributes to knowledge on how we can improve bone marrow failure surveillance in SDS
Welcome to our timely updates on all things SDS, Science, and Advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email genetics@SDSAlliance.org or message us on Facebook! This is all for you!
Framework for Risk-Stratification of Bone Marrow Failure Surveillance in SDS
At the end of the summer, Dr. Warren and colleagues in the United Kingdom published results from an important study of theirs which helps explain why individuals with SDS are at such high-risk for developing bone marrow failure and leukemia and how we can improve bone marrow surveillance. Dr. Warren's work helps build upon research previously published by Drs. Shimamura and Reilly regarding bone marrow failure surveillance in inherited bone marrow failure syndromes (featured in our SDS & Science Snapshot Series earlier this year!).
We reached out to Dr. Warren to bring you an exclusive summary of their work.
Here is what they shared:
This study examined the DNA of blood cells from 10 people with Shwachman-Diamond syndrome (SDS) to see how their blood cells change over time. The work shows that many blood cells in SDS acquire mutations that converge on the genes involved in making ribosomes (the machines that make proteins in the cell) or are components of the machinery that senses the integrity of the ribosome assembly process.
The acquired mutations were recurrent, mutually exclusive between different colonies and arise early in life, even in utero and may then persist for decades. Only a limited set of blood stem cells are producing about half the total number of blood cell colonies by young adulthood. These findings explain why the blood system in SDS is particularly vulnerable to cancer due to loss of function mutations in a gene called TP53, the so called “guardian of the genome” that normally protects against cancer. The study also noted that blood cancer cells in SDS have an increased overall number of mutations, likely reflecting the capacity of these cells to grow rapidly.
This study forms a framework for better risk-stratification in SDS, where patients merit close monitoring of emergent clones. Given the large number of single-hit TP53 clonal expansions that many SDS individuals have, each potentially serving as a substrate for evolution to blood cancer and the very rapid outgrowth and genomic evolution observed following the acquisition of TP53 mutations, consideration for early therapeutic intervention, such as bone marrow transplantation, may be warranted.
a Defective germline ribosome assembly in SDS causes cellular stress, resulting in accumulation of TP53 clones and increased cell death.
b Adaptive somatic mutations can help restore ribosome homoeostasis and decrease accumulation of pathogenic TP53 mutations that would result in clonal evolution.
For more information regarding clones and clonal hematopoiesis, please refer to our video (2021), SDS Science SPOTLIGHT Series: Clones - The Good, the Bad, and the Ugly.
Convergent somatic evolution commences in utero in a germline ribosomopathy.
Machado HE, Øbro NF, Williams N, Tan S, Boukerrou AZ, Davies M, Belmonte M, Mitchell E, Baxter EJ, Mende N, Clay A, Ancliff P, Köglmeier J, Killick SB, Kulasekararaj A, Meyer S, Laurenti E, Campbell PJ, Kent DG, Nangalia J, Warren AJ.
Nat Commun. 2023 Aug 22;14(1):5092.