Research News

Research co-led by pediatric hematologist-oncologist Richa Sharma, MD, has identified a new inherited genetic cause of bone marrow failure: MDM4.

Dr. Sharma’s research was published in Blood and highlighted as a plenary paper, a designation reserved for research findings that are especially significant and impactful. An accompanying commentary underscores the importance of the findings and notes an emerging family of bone marrow failure syndromes.

Researchers believe the identification of MDM4 expands biological understanding of bone marrow failure and may provide answers for patients with unexplained causes of the disease.

Uncommon condition with many genetic causes

Bone marrow, the tissue inside bones, contains stem cells that produce blood cells and platelets every day. Bone marrow failure, which can be inherited or a complication of other medical conditions, occurs when the body is unable to produce enough healthy blood cells.

Although there are more than 80 genes known to cause inherited bone marrow failure syndromes, some patients’ cases remain unexplained. Many cases appear in childhood, sometimes presenting as a child whose development isn’t progressing as expected or whose physical exam identifies abnormalities. Others aren’t diagnosed until adulthood, including those who get diagnosed at an earlier-than-normal age with diseases like myelodysplasia, pulmonary or liver fibrosis, or some types of cancer. Most patients with bone marrow failure require bone marrow transplant or solid organ transplant — major procedures that are associated with poor outcomes.

Pediatric patients, Dr. Sharma believes, are an important population to study since inherited bone marrow failure disorders tend to present with abnormal clinical features in childhood. When a child has visited their pediatrician or other physicians due to issues with blood counts and cancer has been ruled out, she stresses the importance of searching for underlying causes of bone marrow failure disorders. Diagnosing this inherited disease may impact other family members, who may or may not carry the same genetic mutation and be at risk for disease.

A previous study suggested that the MDM4 gene could be a potential link to bone marrow failure. Dr. Sharma, along with more than 20 researchers across the world, compiled all the families and cases with germline MDM4 mutations to establish MDM4 as a gene that contributes to inherited bone marrow failure syndrome.

An influential gene for many to ‘think about’

The researchers identified six unrelated patients from different countries who all had unusual blood counts and bone marrow findings. The patients varied in age of disease diagnosis and comorbidities.

Using multiple methods of lab testing, including gene-editing experiments and stem cell modeling of the MDM4 mutations found in the patients, they identified one common thread across all six patients: overactive p53, a genome guardian and tumor suppressor.

Dr. Sharma believes the implications of this discovery reach far across clinicians and patients — not only for diagnosis and treatment, but also for the importance of research.

“Though it is a relatively uncommon diagnosis, bone marrow failure syndromes impact patients of all ages, and our findings highlight MDM4 as a gene that clinicians should think about when they see pediatric or adult patients presenting with abnormal blood counts and bone marrow features,” she says.

She stresses that the team’s discovery is particularly important for pediatric clinicians and researchers.

“Not only does the study of rare diseases like bone marrow failure reveal fundamental biology that helps us understand other conditions,” Dr. Sharma concludes, “it helps lead clinicians and patients to the answers and potential treatment options they hope for.”