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Rasika Venkataraman, a third-year doctoral student working in the lab of Stanley Lee, PhD, at Fred Hutch Cancer Center, has been honored with the 2024 ASH Graduate Hematology Award for her research on genetic predisposition linked to the gene DDX41 and its connection to hematological diseases.
The American Society of Hematology (ASH), the world’s largest professional society of hematologists, bestows the award to graduate students pursuing careers in academic hematology who are making outstanding contributions to the field. The award will provide Venkataraman with an annual stipend of $40,000, which will be used to further her research over the next two years.
“I’m incredibly honored to receive this award. It will allow me to deepen my research into the molecular mechanisms behind hematological diseases and contribute to the development of more effective treatments for patients,” said Venkataraman.
What can happen if DDX41 mutates
People who have germline (inherited) mutations or defects in their DDX41 gene are at increased risk for developing myelodysplastic syndromes (MDS), which are a group of blood disorders where the bone marrow does not make enough healthy blood cells.
When mutations occur in the DDX41 gene, they can disrupt the gene's function, which can stifle blood cell formation in the bone marrow, leading to marrow failure disorders such as MDS. Not everyone with a DDX41 mutation will develop MDS and not many people in the general population have the mutation. However, if they are born with it, the risk of developing a blood disease is significantly elevated compared to the general population.
Challenges and opportunities
Another challenge related to understanding DDX41 is the fact that most people with an inherited DDX41 mutation have no symptoms until they reach the ages of 65 or older. Then early signs of the disease begin to appear such as fatigue, increased infections and decreased blood clotting.
Venkataraman explained that around age 65, more than half of the people who already have an inherited DDX41 mutation will gain an additional mutation in the second copy of the DDX41 gene.
“We don’t know why, but when it happens, people tend to develop aggressive blood cancer. My project involves studying this, as well as looking more closely at the function of DDX41 and how it leads to blood cancer,” she said.
To do her investigative work, Venkataraman studies RNA splicing, one of the processes in the cell that is thought to be affected by DDX41. Splicing involves removing unnecessary parts of the premature messenger RNA (also known as pre-mRNA) molecule after it is copied from DNA, to make proteins that govern how the body functions.
By studying how these molecular underpinnings of DDX41 mutations can lead to disease, Venkataraman is gaining new insights that can contribute to new approaches and therapies for patients who are impacted by a DDX41 mutation.
In addition to the honor of receiving the award itself, Venkataraman is also excited because the ASH funding will allow her to source more blood and bone marrow samples from patients who have the mutation — a challenge that until now had caused some limitations in what she was able to do. With these samples, Venkataraman aims to use leading-edge techniques like single-cell RNA sequencing, which allows for interrogation of RNA splicing in individual cells of the patient sample thus revealing the basis of the role of DDX41 in disease progression.
Exceptional insight, skills and determination
Venkataraman joined the Stanley Lee Lab in July 2021. At this time, more researchers were becoming interested in DDX41, but there were still several promising areas of research that had been as yet unexplored. One, which Venkataraman pursued, was looking at the differences in the function of the inherited DDX41 mutations compared to those acquired later in life. This led to the discovery that there are specific differences in these mutations, and Venkataraman is studying how these differences lead to MDS.
As Venkataraman continues to build on this foundation, Lee remains confident that Venkataraman’s research has the potential to answer several long-standing questions that have puzzled the field for the past decade.
“Rasika has demonstrated exceptional insight, outstanding technical skills and unwavering determination in her approach to the project," he said. "She has set up elegant experimental systems that allow her to rigorously interrogate the function of DDX41, which has been difficult to study due to its multifaceted roles in cellular biology. Her ability to adapt and innovate within this challenging project has been and will be crucial to advancing our understanding of DDX41 and its roles in blood disorders."
Lee also credits ASH with launching the Graduate Hematology Award program, which began in 2022, because it not only recognizes outstanding PhD graduate students, but it also underscores the critical need for supporting more basic science researchers in hematology.
Venkataraman’s research aligns with current trends in hematology, where the field is moving toward more personalized approaches to treating blood cancers. By investigating the genetic causes of hematological diseases, Venkataraman’s work is contributing to the broader effort to develop targeted therapies that are better suited to the genetic profiles of individual patients.
