Maladaptive somatic gene rescue as predisposition to JAK2 molecular abnormalities? Insights from an Israeli family

Eosinophilia associated with PCM1::JAK2 fusion and classic Philadelphia (Ph)-negative myeloproliferative neoplasms (MPN) are both clonal disorders caused by a dysregulation of the JAK2 signaling pathway. The myeloid neoplasm with t(8;9)(p22;p24.1) and PCM1::JAK2 rearrangement is now formally included among the myeloid/lymphoid neoplasms with eosinophilia (M/LN-eo) and tyrosine kinase fusion genes. To date, no data on genetic predisposition to M/LN-eo with PCM1::JAK2 rearrangement are known, while it is well recognized that a subset of classic Ph-negative MPN segregates within families, suggesting a role for germline predisposition in disease etiology. Here we report the first pedigree with a case of classic Ph-negative MPN and a case of M/LN-eo with PCM1::JAK2. Our patient carried two acquired molecular abnormalities involving JAK2 gene (PCM1::JAK2 fusion and JAK2 H531Y) along with a germline mutation (BLM Y736fs*5, variant allele frequency VAF 41.7%), whereas his sister had the canonical JAK2 V617F driver mutation. This particular pedigree could arise the hypothesis of a genetic predisposition to acquire different JAK2 molecular abnormalities as a maladaptive somatic genetic rescue of an underlying germline predisposition, namely the germline BLM Y736fs*5 mutation.