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<p>JAK (Janus Kinase) inhibitors, such as ruxolitinib, were introduced a decade ago for treatment of myeloproliferative neoplasms (MPN). To evaluate ruxolitinib’s impact on MPN clonal evolution, we interrogate a myelofibrosis patient cohort with longitudinal molecular evaluation and discover that ruxolitinib is associated with clonal outgrowth of RAS pathway mutations. Single-cell DNA sequencing combined with ex vivo treatment of <i>RAS</i> mutated CD34<sup>+</sup> primary patient cells, demonstrates that ruxolitinib induces <i>RAS</i> clonal selection both in a JAK/STAT wild-type and hyper-activated context. <i>RAS</i> mutations are associated with decreased transformation-free and overall survival only in patients treated with ruxolitinib. In vitro and in vivo competition assays demonstrate increased cellular fitness of <i>RAS-</i>mutated cells under ruxolitinib or <i>JAK2</i> knock-down, consistent with an on-target effect. MAPK pathway activation is associated with <i>JAK2</i> downregulation resulting in enhanced oncogenic potential of <i>RAS</i> mutations. Our results prompt screening for pre-existing <i>RAS</i> mutations in JAK inhibitor treated patients with MPN.</p>

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JAK2 inhibition mediates clonal selection of RAS pathway mutations in myeloproliferative neoplasms

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月8日

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  • Nabih Maslah,
  • Nina Kaci,
  • Blandine Roux,
  • Gabriela Alexe,
  • Raphael Marie,
  • Hélène Pasquer,
  • Emmanuelle Verger,
  • Rafael Daltro De Oliveira,
  • Cécile Culeux,
  • Bochra Mlayah,
  • Nicolas Gauthier,
  • Fanny Gonzales,
  • Lin-Pierre Zhao,
  • Saravanan Ganesan,
  • Panhong Gou,
  • Frank Ling,
  • Juliette Soret-Dulphy,
  • Nathalie Parquet,
  • William Vainchenker,
  • Emmanuel Raffoux,
  • Rose Ann Padua,
  • Stéphane Giraudier,
  • Caroline Marty,
  • Isabelle Plo,
  • Camille Lobry,
  • Kimberly Stegmaier,
  • Alexandre Puissant,
  • Jean-Jacques Kiladjian,
  • Bruno Cassinat,
  • Lina Benajiba

摘要

JAK (Janus Kinase) inhibitors, such as ruxolitinib, were introduced a decade ago for treatment of myeloproliferative neoplasms (MPN). To evaluate ruxolitinib’s impact on MPN clonal evolution, we interrogate a myelofibrosis patient cohort with longitudinal molecular evaluation and discover that ruxolitinib is associated with clonal outgrowth of RAS pathway mutations. Single-cell DNA sequencing combined with ex vivo treatment of RAS mutated CD34+ primary patient cells, demonstrates that ruxolitinib induces RAS clonal selection both in a JAK/STAT wild-type and hyper-activated context. RAS mutations are associated with decreased transformation-free and overall survival only in patients treated with ruxolitinib. In vitro and in vivo competition assays demonstrate increased cellular fitness of RAS-mutated cells under ruxolitinib or JAK2 knock-down, consistent with an on-target effect. MAPK pathway activation is associated with JAK2 downregulation resulting in enhanced oncogenic potential of RAS mutations. Our results prompt screening for pre-existing RAS mutations in JAK inhibitor treated patients with MPN.