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SDS & Science Snapshots (2023-01-14)

In this issue: Comprehensive review article on bone marrow surveillance of SDS patients by Drs. Shimamura and Reilly; and a recap of ASH 2022, the biggest annual professional conference on hematology in the world.

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 or message us on Facebook! This is all for you!

New comprehensive review article on the benefits and need for bone marrow surveillance in SDS patients

Fresh off the press, a new review article by Dr. Shimamura and Dr. Reilly was published on December 21, 2022, titled Predisposition to myeloid malignancies in Shwachman-Diamond syndrome: Biological insights and clinical advances.

This is a detailed review article that summarizes many of the key features and challenges in SDS, in particular the leukemia risk, bone marrow biopsies for monitoring, and transplant considerations.

As we all know, Shwachman-Diamond syndrome (SDS) is an inherited multisystem ribosomopathy characterized by exocrine pancreatic deficiency, bone marrow failure, and predisposition to myeloid malignancies. The article provides an overview of the pathobiology of SDS, which is a scientific term for the mechanism within the cell that causes the problems in SDS as a result of the mutations underlying SDS. SDS results from impaired ribosome maturation, i.e. the cell is not able to assemble as many ribosomes as it normally needs. We have created a video about this previously.

The article highlights that the outcomes for SDS patients who develop myeloid malignancies (i.e. acute myeloid leukemia, AML, a specific type of blood cancer) are still extremely poor. This is because SDS patients are highly sensitive to chemotherapy and also because this type of leukemia is a very hard to treat in general and often comes back even after a successful hematopoietic stem cell transplant (HSCT).

Data from the North American SDS Registry indicate that outcomes are improved for SDS patients who undergo routine bone marrow surveillance - i.e. bone marrow biopsy and aspiration and then examining the samples with several kinds of tests - and receive a HSCT prior to developing leukemia. This article sets the stage to evaluate what the optimal approach to hematologic surveillance and timing of HSCT for SDS patients may be, what to look for, and what types of testing are recommended.

The article also summarizes recent studies regarding the distinct patterns of somatic blood mutations in SDS patients that either alleviate the ribosome defect by somatic rescue (heterozygous EIF6 inactivation) or disrupt cellular checkpoints resulting in increased leukemogenic potential (heterozygous TP53 inactivation). This concept is complex but really important in SDS. If you would like to learn more, check out our video from 2021: Clones in SDS: The good, the bad, and the ugly.

The article presents and summarizes evidence supporting hematologic surveillance for SDS patients that incorporates clinical, pathologic, and molecular data to risk-stratify patients and prioritize transplant evaluation for SDS patients with high-risk features.

The field of clonal hematopoiesis - especially when it comes to genetic predisposition to malignancy such as SDS - is fairly new. We would like to thank Dr. Shimamura, Dr. Reilly, and Dr. Lindsley, for the groundbreaking work in this area and their efforts to provide these insights and spread awareness to the medical community. Looking into the future, we need the international hematology and SDS community to come together and develop a consensus on how SDS patients should be monitored, what genetic changes should be tested and what they mean, so that all patients - regardless of where they are - can be confident that they receive adequate care. We are ready to support the process.

Additionally, we are calling on all SDS patients to consider participating in the North American SDS Registry and all other clinical registries in their geographic area to support important work such as this. A list on clinical registries is available on our website, here:

The full-text article is currently behind a paywall, but the abstract is publicly available. Please reach out if you need access to the full text. [Update: as of summer 2023, the article is now available open access using the same links posted here]

Reilly CR, Shimamura A. Blood. 2022 Dec 21:blood.2022017739.

doi: 10.1182/blood.2022017739. Online ahead of print. PMID: 36542827

Recap of ASH 2022

The 64th American Society of Hematology (ASH) Annual Meeting was held last month, from December 10-13 in New Orleans, Louisiana.

Dr. Hars, as a representative of the SDS Alliance Non-Profit Patient Advocacy Organization, have been awarded complimentary registration to the 2022 ASH Annual Meeting & Exhibition (a $1,500 value) as an appreciation of our organizations’ continued effort and dedication to the patients and the field of hematology. We would like to thank the organizers of ASH for this opportunity!

According to ASH, there are “typically, more than 5,000 scientific abstracts submitted each year, and more than 3,000 abstracts are accepted for oral and poster presentations through an extensive peer review process.” In fact, doing a quick search on the now publicly available abstracts’ page, we found close to 6,500.

Importantly, there are several abstracts, posters, and talks about SDS or relevant to it. Here is our brief overview.

Related to the review article features above in this week's snapshots article, Ashley Galvin - in collaboration with the North American SDS Registry - presented an oral and poster abstract titled: Outcomes of Hematologic Complications in Shwachman Diamond Syndrome: High Risk Features and Implications for Surveillance

"AML carries a poor prognosis for patients with SBDS mutations, so early referral for novel therapies should be considered. Marrow surveillance including morphology, cytogenetics, FISH, and somatic mutation analysis identified patients who developed HRF (High Risk Features). Survival was excellent for patients transplanted for HRF. Although SDS is rare and patient numbers are small, these data show that regular comprehensive marrow surveillance can identify HRF to inform the need for closer monitoring or transplant prior to progression to malignancy."

SDS was also covered in an Education Program session titled: What is New in Classical Bone Marrow Failure Syndromes? (focus on management)

Inherited bone marrow failure syndromes are a complex set of disorders characterized by single or multilineage cytopenias and elevated risk of hematopoietic and other malignancies. Patients may present with classic phenotypes, such as neutropenia in Shwachman-Diamond Syndrome, but the increased use of germline genetic testing and other diagnostics have led to a growing appreciation of a wide spectrum of IBMFS [inherited bone marrow failure syndromes] clinical phenotypes and ages at onset ranging from children to adults. This educational session explored the clinical manifestations, genetic etiologies, and new avenues for the management of severe congenital neutropenia [including Shwachman-Diamond Syndrome], Fanconi anemia, and telomere biology disorders.

  • Dr. Jean Donadieu (Service d'Hémato-Oncologie Pédiatrique, Hopital Trousseau, Paris, Cedex, France and director of the French congenital neutropenia registry) discussed therapeutic options for severe congenital neutropenias (SCNs) beyond granulocyte colony stimulating factor (GCSF) and hematopoietic cell transplantation, using three different genetic disorders as examples. First, the talk described the rationale for the use of inhibitor of sodium glucose cotransporter (ISGTL2), an anti-diabetic drug, in glycogen-storage disease type-IB and glucose-6-phosphatase catalytic subunit-3 (G6PC3) neutropenias; Second, a potential role of C-X-C chemokine-receptor-4 inhibitors in warts, hypoglobulinemia, infections and myelokathexis (WHIM) syndrome. And third, it discussed the concept of stimulating somatic genetic rescue, a physiological process that might limit the risk of leukemic transformation, like EIF6 inhibitors in Shwachman Diamond Syndrome - an area of focus in several research labs.

  • Dr. Carlo Dufour (G.Gaslini Chidlren's Hospital, Genova, Italy) focused on management of Fanconi Anemia and its clinical complications starting with presenting a case report that outlines the importance of a long-term specific monitoring plan in this setting. The talk will outlined monitoring strategies tailored to timely detect hematological complications in order to perform hematopoietic cell transplantation (HCT) in optimal conditions. The most recently adopted HCT platforms was discussed. This talk also addressed surveillance approaches to identify early cancers, especially epithelial cancers of head and neck and urogenital regions, that currently have no satisfactory treatment.

  • Dr. Sharon Savage (Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD) discussed the numerous genetic discoveries and the advent of clinical telomere length testing that have led to the recognition of a spectrum of telomere biology disorders (TBDs), beyond classic dyskeratosis congenita (DC). While hematopoietic cell transplantation and androgen therapy are effective for bone marrow failure in TBDs, there is a paucity of options for the other manifestations, such as pulmonary fibrosis, liver disease or cancer. This talk highlighted areas in need of additional clinical and basic science research while providing the background for clinical diagnosis and management.

Another way to look at SDS is by comparing it to other neutropenias caused by different genetic disorders. Dr. Maksim Klimiankou (Department of Hematology, Oncology, Clinical Immunology, University Hospital Tuebingen, Tuebingen, Germany) presented an oral and poster abstracts on this topic, titled: Accumulation of Specific Somatic Leukemia-Associated Mutations in Congenital Neutropenia Precedes Malignant Transformation – New Preconditions for Treatment Decisions

There were several abstracts submitted on model systems, namely three on zebrafish and one on mouse:

"We conclude that the organismal models of sbds or eif6 deletion provide new insights into the pathophysiology of human SDS: 1) SBDS affects lipid metabolism possibly due to an accumulation of EIF6, 2) Loss of eif6 affects development/survival at an earlier stage than loss of sbds, and 3) Loss of either sbds or eif6 markedly upregulates cdkn1a, which is downstream of tp53. Interestingly, Eif6 partially rescues survival of sbds-null organisms, but only in the haploinsufficient state. EIF6 may offer a promising target for a novel therapeutic strategy in SDS."

"Zebrafish lacking efl1 phenocopied some of the molecular and morphologic features of SDS. Additionally, results from efl1-/- zebrafish were consistent with those from sbds-/- zebrafish strains, emphasizing a common molecular pathway induced by the dyad of EIF6 dissociating factors. Ongoing studies, which will be presented, are evaluating skeletal abnormalities and pancreatic atrophy in the efl1-/- zebrafish. Interestingly, sbds-null and efl1-null fish survived longer than eif6-null, suggesting more critical functions of EIF6. Altogether our data and presented elsewhere advance the hypothesis that CDKN1A and EIF6 contribute to the pathophysiology of SDS due to either mutations in SBDS or EFL1."

"Our findings suggest that Dnajc21 is required for normal granulocyte differentiation and cell proliferation. We also identified previously unrecognized roles for Dnajc21 in regulating cellular metabolism. We propose that the zebrafish models described here readily serve as in vivo platforms to identify therapeutic compounds that restore normal hematopoiesis and prevent leukemic transformation in SDS."

"[..] Disruption of sequences within this putative ISS by Cas12a nuclease-mediated indels result in 1.4 and 2.4 fold increased SBDS/Sbds expression from SDS patient fibroblasts and homozygous MEFs respectively (p<0.05). Together these studies present a novel mouse model for SDS recapitulating the recurrent SS mutation with residual intact splicing and indicate that salvaging residual SBDS expression by modulating aberrant splicing is a promising strategy for SDS therapeutics."

We applaud all the researchers from around the world who work on SDS and bring us closer to therapies and cures. A heartfelt THANK YOU on behalf of the SDS Alliance and the patient community!

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