No physician looks forward to telling a family their child has leukemia. The experience is especially challenging when the child develops leukemia due to Shwachman-Diamond syndrome (SDS) since outcomes are dismal. These conversations motivate Kasiani Myers, MD, to understand SDS at a deep molecular level. Myers is a pediatric hematologist and researcher with the Division of Bone Marrow Transplantation and Immune Deficiency. She recently was part of a translational study with colleagues from Boston Children’s Hospital that provided insight into the genetic underpinnings of leukemic development in SDS. The study’s findings could lead to better screening strategies, new diagnostic tests and targeted therapies for SDS.

SDS is a rare, inherited disease predominantly caused by biallelic germline mutations in the SBDS gene. In SDS, ribosomes do not assemble correctly, leading to comorbidities, including bone marrow failure, pancreatic insufficiency, and neuropsychological and skeletal issues. About 40% of people with SDS develop myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in the first several decades of life.

“Survival of people with SDS who develop blood cancers is poor because often if the disease is that advanced, even a bone marrow transplant may not be curative,” Myers says. “If we knew a child with SDS had developed higher-risk features concerning for MDS or AML development, we could do an early allogeneic stem cell transplant and potentially save their life.”

The study, published in Nature, tested bone marrow samples from 110 SDS patients using single-cell DNA sequencing. The researchers observed longitudinal changes in somatic mutations that lead to leukemic development—in some cases, changes over 10 years. They collected samples from the North American Shwachman-Diamond Syndrome Registry, which Myers co-directs with Akiko Shimamura, MD, PhD, a bone marrow failure specialist at Boston Children’s. The study found that the most commonly and independently mutated genes in SDS were EIF6 and TP53 and that multiple, distinct somatic clones develop at an early age.

The study also explored the mechanistic function of the TP53 and EIF6 mutations. TP53 mutations are more leukemia prone and inactivate tumor suppression checkpoints. EIF6 mutations have limited leukemia potential—in fact, they decrease TP53 activation, alleviate the underlying SDS ribosome defect and may enhance clone fitness. The presence of TP53 mutations in both alleles is strongly associated with leukemic development.

Clinical laboratories do not test for the biallelic TP53 gene mutation. Myers and her colleagues hope to develop a clinical test based on next-generation sequencing that would allow physicians to track changes in the mutated genes longitudinally.

“Current screening recommendations include annual bone marrow testing, but by the time we see changes on the standard bone marrow testing, disease can be very advanced and limit successful treatment with transplant,” Myers says. “Our test would look for new and evolving changes in genes associated with a high risk for MDS or AML. Considered in the context of bone marrow screening results, these test results will allow us to target high-risk kids and transplant them early, which could dramatically improve outcomes and change the trajectory of their lives.”

The North American Shwachman-Diamond Syndrome Registry began about 15 years ago and includes over 360 patients enrolled in 43 states and 10 countries. In addition to focusing on the early diagnosis of leukemia predisposition in SDS, researchers are using the registry to improve transplant strategies and develop more effective therapies for patients with AML in inherited bone marrow failure syndromes.

To learn more about the registry or this study, contact Kasiani Myers.