In this issue: Dr. Alan Warren's group reviews cutting edge research on clonal hematopoiesis and its impact on personalized medicine opportunities for SDS.
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Understanding the Role of Blood and Bone Marrow Stem Cell Mutations and Their Impact on SDS Progression and Treatment
Shwachman-Diamond Syndrome (SDS) is a rare genetic disorder that affects the bone marrow, pancreas, and skeletal system. Recently, researchers have made significant strides in understanding how somatic (or acquired) genetic mutations play a role in the bone marrow failure of patients with SDS. Dr. Alan Warren and his team recently published a review of these advancements in Blood, the official journal of the American Society of Hematology.
One study highlighted in this review used advanced techniques to map relationships between the blood and bone marrow stem cells in patients with SDS, shedding light on the mutations that may influence the development and progression of MDS and AML. This was done by analyzing individual stem cells from the blood and bone marrow of ten SDS patients aged 4 to 33 years. Researchers discovered that most of these patients had large groups of bone marrow stem cells with a lot of somatic (or acquired) genetic mutations, such as mutations in the TP53 gene, a pattern usually seen in much older individuals. This suggests that blood and bone marrow stem cells in SDS patients are affected early in life, contributing to the development of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) at younger ages.
Another recent finding highlighted by this review, was the role of acquired (somatic) mutations and how the different somatic mutations interact. While acquired (somatic) mutations were common in the blood and bone marrow stem cells of patients with SDS, not all somatic mutations led to severe consequences. Interestingly, some somatic mutations seemed to help cells survive better despite the SDS-related defects. These "rescue" mutations potentially lower the risk of disease progression to MDS or AML. However, when acquired TP53 mutations occur in both copies of the gene, it can lead to severe conditions like MDS or AML. For more information regarding the development of clones and the difference between somatic and germline variants, watch the video below or review these previously published SDS & Science Snapshots (Somatic and Germline Variants or The Difference between Germline and Somatic Genetic Testing).
The review published by Dr. Warren and his team shared that multiple recent studies have had similar findings, reporting that up to 72% of SDS patients often develop clonal hematopoiesis (CH). CH happens when some blood and bone marrow stem cells with specific “signatures” of acquired (or somatic) mutations start to dominate, but other features of MDS and AML are not present in the bone marrow. The acquired CH mutations observed in SDS patients were usually different from those seen in older adults without SDS. By tracking these mutations over time, researchers hope to better understand how they affect disease progression from CH to MDS and AML. For more information about clones, how they develop, and how to monitor the development of them, watch the video below.
Dr. Warren and his team emphasized the timing of when these somatic mutations occur is also crucial. By building a "family tree" of stem cell mutations, researchers can estimate when specific mutations happened. Some mutations in SDS patients can occur very early, even before birth. Following the “family tree” of somatic mutations and how they relate to early somatic mutations highlights the importance of monitoring SDS patients from a young age.
Dr. Warren presented part of this work and background virtually as part of the 2024 Expert Webinar Series, hosted by our Australian partner organization, Maddie Riewoldt's Vision, focused on funding research to discover cures for Bone Marrow Failure Syndromes.
For families and patients with SDS, these findings emphasize the importance of regular bone marrow biopsies and somatic genomic testing (also known as NGS) on these bone marrow biopsy samples and/or on peripheral blood samples. Understanding which somatic mutations are present in the blood and bone marrow of SDS patients can help doctors predict the risk of disease progression and make informed decisions about treatments, including the potential of bone marrow transplant. As research advances, it may also lead to new therapies that target specific somatic mutations or pathways, offering hope for better outcomes in the future.
Cull AH, Kent DG, Warren AJ. Emerging genetic technologies informing personalized medicine in SDS and other inherited bone marrow failure disorders. Blood. 2024 Jun 21:blood.2023019986. Epub ahead of print. PMID: 38905596.
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