The definition of the “best” can be subjective, but innovative, collaborative science that can translate to improved patient outcomes is a great benchmark. The myelodysplastic syndromes (MDS) are the most common acquired adult bone marrow failure syndromes.1 While our understanding of MDS molecular pathophysiology has dramatically increased in the past decade, we still have not moved toward therapies that meaningfully transform the patient prognosis. One large factor that may underlie this poor track record is that we still lack truly novel insights into the biology of MDS to inform future advancements in MDS treatment paradigms. Perhaps, as seen here, we will need the children to teach the adults.
Unlike adult cases, most patients with childhood MDS carry a gene mutation associated with MDS predisposition. These mutations are either inherited or arise spontaneously as germline. There is a great deal that MDS predisposition syndromes can teach us about acquired MDS in older and younger patients. This current selection for the Year's Best of 2021 involves a body of work incorporating multiple techniques to highlight novel insights for MDS and how we can approach the next decade of work, and beyond, to understand and target biology in MDS.
Mutations in SAMD9 and SAMD9L were found to cause hereditary forms of MDS with high rates of loss of chromosome 7 in the bone marrow.2 Mutations in SAMD9 that enhance activity of SAMD9 protein predispose to early childhood MDS and to further syndrome features called MIRAGE.3 Interestingly, mutations in SAMD9/SAMD9L that lead to loss of protein function also cause MDS, but mainly in adults. The observation that both increasing or decreasing activity of proteins encoded by SAMD9/SAMD9L predispose to MDS suggests that understanding SAMD9/SAMD9L function is critical to understanding MDS biology. Another recent interesting finding in the field is an increasing awareness of somatic rescue mosaicism in marrow failure syndromes.4 This is a rare spontaneous event in which a somatic mutation offsets the effect of a pathogenic germline mutation. Somatic rescue mosaicism is a naturally occurring “gene therapy” in which a pathogenic germline mutation is corrected by an acquired event. This spontaneous phenomenon, sometimes called somatic genetic rescue (SGR), gives rise to multiple cell populations within single organisms, which can improve clinical phenotype. This may be something we can ultimately truly understand and harness therapeutically for adults and children alike.
In a landmark international study5 led by Dr. Sushree Sahoo and colleagues published in Nature Medicine, an international collaboration of researchers investigated the clinically annotated EWOG-MDS consortium pediatric cohort (n = 669) amassed throughout the past 20 years. In this useful cohort of retrospective patients, the authors identified the prevalence, genetic landscape, phenotype, therapy outcome, and clonal architecture of SAMD9/SAMD9L syndromes. Germline SAMD9/SAMD9L mutations accounted for 8 percent and were mutually exclusive, with GATA2 mutations present in 7 percent of the cohort. Previously, it was thought that GATA2 was the most common predisposition in pediatric MDS.6 Refractory cytopenia was the most prevalent MDS subtype (90%); acquired monosomy 7 was present in 38 percent of the cohort; and immune dysfunction was present in 28 percent, illustrating that the manifestations are not limited to the hematologic system alone. With the use of single-cell analysis techniques, data reveal that pediatric patients carrying germline SAMD9/SAMD9L mutations can potentially self-correct through SGR. Sixty-one percent of SAMD9/SAMD9L– mutated patients underwent SGR resulting in clonal hematopoiesis, of which 95 percent was maladaptive (monosomy 7 ± cancer mutations) and 51 percent had adaptive nature (clinically protective).
This pivotal study illustrates a pathway for study in myeloid malignancies that is very appealing as a paradigm. To begin, we can attain improved understanding of the natural history of rare (or common) conditions through access to well-annotated biospecimens linked to robust clinical and molecular data. Large consortia and international collaborations can advance science at faster rates as well. This is true for most diseases but is especially so in MDS. Detailed biologic insight in pediatric germline MDS can teach us more about pathways and clonal events that may ultimately apply to the field as a whole. Additional knowledge of somatic rescue mosaicism in pediatric marrow syndromes7 might give clues to phenotypic expression and improve therapeutic stratification. Whether or not this is something we can engineer as “adaptive” for adults certainly remains a question but could allow for potentially averting higher-risk therapies in pediatric patients where possible. A challenge in MDS is that only a handful of mutations in acquired disease are gain-of-function mutations whereas SAMD9 and SAMD9L syndromes are caused by heterozygous (mostly missense) mutations that predispose to MDS with monosomy 7. These are gain-of-function mutations, and their strong growth-suppressive nature facilitates the selection of hematopoietic clones that underwent SGR. This may limit some extrapolation to all MDS but still teach us about what we can improve when we know we have a gain-of-function mutation in acquired MDS. Single-cell sequencing is increasingly used to detect myeloid malignancies in research, and hopefully soon in clinical realms for additional patient use. Future applications of this work beyond 2021 will likely consist of more assessment of clonality than ever, observations of somatic rescue mosaicism, and perhaps additional translation of germline findings to the acquired cancer realm.
Competing Interests
Dr. DeZern indicated no relevant conflicts of interest.
