The discovery, led by researchers at Dana-Farber, could pave the way for interventions to reduce the risk of blood cancers among people with sickle-cell disease.
A large-scale genomic analysis, led by investigators at Dana-Farber Cancer Institute, has uncovered a strong association between sickle-cell disease and the early development of clonal hematopoiesis, a precancerous condition known to raise an individual’s risk of certain blood cancers.
The findings may explain why some people with sickle cell disease are predisposed to developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), particularly after potentially curative treatments such as stem cell transplantation and gene therapy. The findings were presented at the 67th American Society for Hematology Annual Meeting and Exposition on December 6 in Orlando, FL.
Lachelle Weeks, MD, PhD
“This is the largest study of sickle cell disease that's been sequenced directly and at this depth,” said Dana-Farber hematologist-oncologist and co-lead investigator Dr. Lachelle Weeks. “The ability to accurately detect and define the prevalence of clonal hematopoiesis in patients with sickle cell disease opens up the possibility that we may be able to target clonal hematopoiesis in this population to mitigate blood cancer risk.”
“Understanding the biology and frequency of clonal hematopoiesis in people with sickle cell disease is essential as we work to develop treatments that are both effective and safe,” said Dana-Farber physician-scientist and study senior author, Dr. Coleman Lindsley.
Sickle cell disease is an inherited blood disorder that causes red blood cells to become misshapen and fragile. These abnormal cells can obstruct blood vessels, leading to anemia, jaundice, severe pain, and organ failure. People with sickle cell disease have long been observed to face higher risks of MDS and AML, but the reason behind this elevated risk has remained unclear. Only two prior studies have examined whether sickle cell disease increases the risk of clonal hematopoiesis, a precursor state to these cancers, and the findings have been contradictory. This lack of consensus has underscored the need for a large, well-powered study capable of determining whether clonal hematopoiesis is truly more common, and/or develops earlier, in this population.
Coleman Lindsley, MD, PhD
In the new study, the researchers used an ultra-sensitive DNA sequencing method developed by the Lindsley laboratory and Broad Institute collaborators to detect clonal hematopoiesis at levels far below the threshold of standard tests. Using this approach, they compared the rates of clonal hematopoiesis in 3,885 individuals with sickle cell disease to 3,398 individuals with sickle cell trait or normal hemoglobin, and to 188 individuals with a related blood disorder called beta thalassemia. The study population was both geographically and demographically diverse, spanning ages 6 months to 80 years from North America, Brazil, and sub-Saharan Africa.
The researchers found that not only was clonal hematopoiesis more common in people with sickle cell disease, but it also occurred at much younger ages. Among those ages 0-19, clonal hematopoiesis was detected in 10.6% of individuals with sickle cell disease, compared to 3.5% in a predominantly Black control cohort without the disease.
Even among infants as young as 6-16 months, clonal hematopoiesis was detected in 4.7% of those with sickle cell disease. And when samples from the same children were analyzed again years later, all of those early clones were still present. The analysis also revealed that this early-onset of clonal hematopoiesis is primarily driven by mutations in the DNA damage response and repair pathway, rather than by mutations typically associated with age-related clonal hematopoiesis. These findings were unique to sickle cell disease, as researchers did not find an increased prevalence of early-onset clonal hematopoiesis among those with sickle-cell trait or beta thalassemia.
The analysis also revealed that this early-onset of clonal hematopoiesis is primarily driven by mutations in genes involved in the DNA damage response and repair (DDR) pathway, rather than by mutations typically associated with age-related clonal hematopoiesis. Notably, DDR-pathway mutations are also recurrent in leukemias reported in people with sickle cell disease, suggesting a possible biological connection that warrants further study. These findings were unique to sickle cell disease, as researchers did not find an increased prevalence of early-onset clonal hematopoiesis among those with sickle cell trait or beta thalassemia.
Dr. Weeks pointed out that counseling and clinical management of clonal hematopoiesis are relatively new in areas of hematology. "People with sickle cell disease have not traditionally been part of conversations about clonal hematopoiesis, even though they may be uniquely affected,” Dr. Weeks said. “These data highlight the importance of involving this community in future studies and clinical trials focused on understanding clonal hematopoiesis and its potential role in blood cancer risk.
This research was, in part, funded by the National Institutes of Health (NIH) Agreement OTXXXXXXXXX and the CureSC Initiative.