A study identified that the germline JAK2G127D mutation synergizes with the somatic JAK2V617F mutation to drive progression to myelofibrosis in patients with myeloproliferative neoplasms (MPN). Additionally, the JAK2G127D and JAK2V617F mutation synergy significantly potentiated in vitro activation of the JAK-STAT signaling pathway.
Yanjie Lan, MD, PhD, of the Second Hospital of Tianjin Medical University in China, presented the study at the 2026 EHA Congress in Stockholm, Sweden.
The analysis reviewed clinical data and samples from patients with MPN diagnosed at the authors’ center from 2018 to 2025 to characterize the prevalence and impact of JAK2G127D mutations. Next-generation sequencing was used to detect genetic mutations in samples, and cell models were used to evaluate the functional impact of co-occurring mutations. Out of 249 samples positive for JAK2V617F mutations, 15 carried a concurrent JAK2G127D mutation. Notably, JAK2G127D mutations only co-occured with JAK2V617F mutations.
Compared with patients with only JAK2V617F mutation, those with concurrent JAK2V617F and JAK2G127D mutations had significantly shorter myelofibrosis-free survival outcomes (P=.0062) and significantly higher levels of transforming growth factor-beta. In addition, double-mutated patients with advanced disease had higher grades of myelofibrosis and higher JAK2V617F variant allele frequency.
The researchers modeled JAK2 wild type, JAK2V617F, JAK2G127D, and concurrent JAK2V617F and JAK2G127D, in Ba/F3 and 32D cells expressing erythropoietin receptors and found comutation enhanced cytokine-independent cellular proliferation and “markedly” activated the JAK2-STAT5 signaling pathway.
Dr. Lan and colleagues planned to develop a murine model to further investigate the functional role of JAK2G127D in patients with MPN.
Reference
Lan Y, Zhang Y, Teng G, et al. A novel germline JAK2 mutation JAK2G127D cooperation with JAK2V617F to accelerate myelfibrosis progression in MPNS. Abstract #EHA-6219. Presented at the European Hematology Association 2026 Congress; June 11-14, 2026; Stockholm, Sweden.
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