By Patrick Daly - Last Updated: June 12, 2024
Preclinical modeling showed myeloproliferative neoplasms (MPN) depend on mutated JAK2V617F cells, and targeting JAK2V617F suppressed features of MPN, reduced mutant cell fraction, and extended overall survival, according to a study co-led by Andrew Dunbar, MD, and Robert Bowman, PhD, of Memorial Sloan Kettering Cancer Center.
“Our data suggest that JAK2V617F dependency persists even in the setting of antecedent mutations in epigenetic regulators, specifically TET2,” the authors said in a report published in Cancer Discovery.
Based on their findings, the researchers suggested that “improved targeting of aberrant JAK2 signaling and downstream effectors offers greater therapeutic potential than current [Janus kinase (JAK)] inhibitors and that JAK2V617F mutant-selective inhibition represents a potential curative strategy for the treatment of patients with MPN.”
What Is the Best Target for MPN Therapy?
The study’s authors evaluated the role of JAK2V617F mutations in MPN persistence through JAK inhibitor therapy using an inducible dual-recombinase “knock-in/knock-out” mouse model. In the model, targeting JAK2V617F both improved MPN measures and depleted disease-sustaining stem cells.
Overall, “our data suggest JAK2V617F represents the best therapeutic target in MPN and demonstrate the therapeutic relevance of a dual-recombinase system to assess mutant-specific oncogenic dependencies in vivo.”
Reference
Dunbar AJ, Bowman RL, Park YC, et al. Jak2V617F reversible activation shows its essential requirement in myeloproliferative neoplasms. Cancer Discov. 2024;14(5):737-751. doi:10.1158/2159-8290.CD-22-0952
Original Source: Analysis Shows MPN Depend on JAK Mutation for Persistence | Blood Cancers Today