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<p>Eosinophilia associated with <i>PCM1::JAK2</i> 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 <i>PCM1::JAK2</i> 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 <i>PCM1::JAK2</i> 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 <i>PCM1::JAK2</i>. Our patient carried two acquired molecular abnormalities involving <i>JAK2</i> gene (PCM1::<i>JAK2</i> fusion and <i>JAK2</i> H531Y) along with a germline mutation (<i>BLM</i> Y736fs*5, variant allele frequency VAF 41.7%), whereas his sister had the canonical <i>JAK2</i> V617F driver mutation. This particular pedigree could arise the hypothesis of a genetic predisposition to acquire different <i>JAK2</i> molecular abnormalities as a maladaptive somatic genetic rescue of an underlying germline predisposition, namely the germline <i>BLM</i> Y736fs*5 mutation.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月5日

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  • Oscar Borsani,
  • Carmelo Gurnari,
  • Daniela Pietra,
  • Elisa Rumi

摘要

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.