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A novel activating JAK1 mutation in chronic eosinophilic leukemia
William Shomali1, Alisa Damnernsawad2,3, Talent Theparee4
1Division of Hematology, Stanford Cancer Institute/Stanford University School of Medicine, Stanford, CA.
Blood Advances
|September 8, 2021
Summary
A novel JAK1 mutation (R629_S632delinsSA) was identified in a patient with hypereosinophilia (HE). This mutation drives eosinophil survival and can be targeted by JAK inhibitors, offering new insights into chronic eosinophilic leukemia.
Area of Science:
- Hematology
- Molecular Biology
- Oncology
Background:
- Hypereosinophilia (HE) is classified into primary (HEN), secondary (HER), or undetermined significance (HEUS).
- Myeloid next-generation sequencing (NGS) reclassifies some HEUS cases as HEN, including chronic eosinophilic leukemia not otherwise specified (CEL, NOS).
Purpose of the Study:
- To identify and characterize a novel mutation in a patient with HE initially classified as HEUS.
- To investigate the functional impact of the identified mutation on eosinophil survival and the JAK-STAT pathway.
Main Methods:
- Next-generation sequencing (NGS) panel analysis.
- In vitro functional studies using Ba/F3 cell lines.
- Treatment with JAK1/JAK2 inhibitor ruxolitinib.
Main Results:
- A novel somatic JAK1 pseudokinase domain mutation (R629_S632delinsSA) was identified.
- The mutation conferred growth factor independence and activated the JAK-STAT pathway in Ba/F3 cells.
- Ruxolitinib effectively abrogated the mutation-induced effects.
Conclusions:
- R629_S632delinsSA is the first identified somatic JAK1 mutation associated with a clonal eosinophilic neoplasm.
- The JAK-STAT pathway plays a critical role in eosinophil survival in certain myeloid neoplasms.
- Targeting JAK1/JAK2 with inhibitors like ruxolitinib shows therapeutic potential for related conditions.
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