UNDERSTANDING MAP2K1 and MAP2K2 Gene Changes in Hairy Cell Leukemia
Poster hall during ASH 2025 Annual Meeting
At the 2025 Annual Meeting of the American Society of Hematology (ASH), researchers shared new findings that help us better understand HCL and why the disease can act differently in some people. In this second post of our ASH 2025: HCL Takeaways series, we focus on a study led by researchers from the National Cancer Institute, NIH. The research looks at genetic changes in two genes, MAP2K1 and MAP2K2, that may affect how certain forms of HCL develop and respond to treatment. Evgeny Arons, PhD, from the Laboratory of Molecular Biology and a member of Senior Investigator Robert J. Kreitman, MD’s team, presented the study at the ASH meeting.
Why Genes Matter in Hairy Cell Leukemia (HCL)
Most people with HCL have a specific change in the BRAF gene called BRAF V600E. Finding this mutation changed how researchers understand the disease and led to targeted treatments that help many patients.
However, some patients, especially those with Hairy Cell Leukemia Variant (HCLv) or other ultra rare types of HCL, do not have the BRAF mutation. Researchers are looking for other genetic changes that might explain how the disease starts in these cases.
This study looked at two genes in the MAPK signaling pathway, which helps control how cells survive. Changes in this pathway can make it easier for cancer cells to grow and divide.
Research Methods
Researchers studied genetic data from 225 patients with HCL or HCL variant using advanced sequencing methods, such as whole-exome and next-generation sequencing.
To get accurate results, the team carefully separated leukemia cells from patient samples before testing. They then checked for mutations in MAP2K1 or MAP2K2, which are genes that make proteins in the MAPK signaling pathway.
To learn how these mutations affect leukemia cells, scientists made lab models by adding specific MAP2K1 mutations to B-cell lines. These models helped researchers see how the mutations change cell growth and signaling.
Key Takeaways
1. MAP2K1 mutations occur in some patients without BRAF mutations
The study found 26 different MAP2K1 genetic changes in 52 patients whose leukemia did not have the usual BRAF mutation. These changes were seen in both HCL and HCL variant cases.
Two mutations, K57N and C121S, were among the most common.
2. MAP2K2 mutations were discovered in HCL for the first time
Researchers also found MAP2K2 mutations, which had not been reported before in HCL or HCL variant. Although these mutations are less common, the findings help expand what we know about the genetic causes of the disease.
3. Certain genetic patterns may indicate higher-risk disease
Patients with MAP2K1 mutations were more likely to have other high-risk features, such as:
Unmutated IGHV genes
IGHV4-34 gene usage
Hairy Cell Leukemia Variant phenotype
In the study, patients with these mutations had a shorter time to next treatment compared to patients whose disease only had the BRAF mutation.
4. Laboratory models help identify potential future treatments
By using cell models with MAP2K1 mutations, researchers saw that key signaling pathways, including MEK and ERK (parts of the MAPK pathway), became active.
These models may help scientists test current targeted drugs and create new treatments for patients whose disease has these mutations.
What this Means for People Living with HCL
This research shows that at the molecular level, Hairy Cell Leukemia is not just one disease. Most patients have the BRAF mutation, but others have different genetic changes that can affect how the disease acts.
For patients, these discoveries may one day help to:
Improve diagnosis of unusual HCL cases
Identify patients who may benefit from different treatment strategies
Guide the development of new targeted therapies
Most importantly, this research is helping move the field toward more personalized treatments for people living with HCL.
Looking Ahead
Researchers at the NIH and partner institutions continue to study these rare genetic mutations and test therapies that might target the MAPK signaling pathway. As research continues, it could lead to more treatment options for patients with BRAF-negative HCL or HCL variant. For now, these findings are still under study and do not change standard treatment for most patients.
At the Hairy Cell Leukemia Foundation, we are committed to translating complex scientific findings into clear information for patients.
Stay tuned for more posts in our ASH 2025: HCL Takeaways series, where we will continue to share research that is shaping the future of HCL care.