A novel activating JAK1 mutation in chronic eosinophilic leukemia

Hypereosinophilia (HE) has been defined as persistent eosinophilia .1.5 3 10⁹/L; it is broadly divided into primary HE (clonal or neoplastic; HE_N), secondary/reactive HE (HE_R), or HE of undetermined significance (HE_US) 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 HE_US, reassigning some patients to the category of HE_N, 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.