A novel activating JAK1 mutation in chronic eosinophilic leukemia

Blood Adv. 2021 Sep 28;5(18):3581-3586. doi: 10.1182/bloodadvances.2021004237.


Hypereosinophilia (HE) has been defined as persistent eosinophilia >1.5 × 109/L; it is broadly divided into primary HE (clonal or neoplastic; HEN), secondary/reactive HE (HER), or HE of undetermined significance (HEUS) when no cause is identified. The use of myeloid next-generation sequencing (NGS) panels has led to the detection of several mutations in patients previously diagnosed with HEUS, reassigning some patients to the category of HEN, specifically the World Health Organization category of chronic eosinophilic leukemia, not otherwise specified (CEL, NOS). Here, we describe a novel somatic JAK1 pseudokinase domain mutation (R629_S632delinsSA) in a patient with HE that had initially been characterized as a variant of uncertain significance. We performed functional studies that demonstrated that this mutation results in growth factor independence of Ba/F3 cells in vitro and activation of the JAK-STAT pathway. These effects were abrogated by the JAK1/JAK2 inhibitor ruxolitinib. R629_S632delinsSA is the first known somatic mutation in JAK1 linked to a clonal eosinophilic neoplasm, and highlights the importance of the JAK-STAT pathway in eosinophil survival.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Hypereosinophilic Syndrome* / diagnosis
  • Hypereosinophilic Syndrome* / drug therapy
  • Hypereosinophilic Syndrome* / genetics
  • Janus Kinase 1 / genetics
  • Leukemia*
  • Mutation
  • Protein Kinase Inhibitors / therapeutic use


  • Protein Kinase Inhibitors
  • JAK1 protein, human
  • Janus Kinase 1

Supplementary concepts

  • Pdgfra-Associated Chronic Eosinophilic Leukemia