OncoImmunology (Oct 2017)

Mutations in JAK2 and Calreticulin genes are associated with specific alterations of the immune system in myelofibrosis

  • Marco Romano,
  • Daria Sollazzo,
  • Sara Trabanelli,
  • Martina Barone,
  • Nicola Polverelli,
  • Margherita Perricone,
  • Dorian Forte,
  • Simona Luatti,
  • Michele Cavo,
  • Nicola Vianelli,
  • Camilla Jandus,
  • Francesca Palandri,
  • Lucia Catani

DOI
https://doi.org/10.1080/2162402X.2017.1345402
Journal volume & issue
Vol. 6, no. 10

Abstract

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Myelofibrosis (MF) is a clonal neoplasia associated with chronic inflammation due to aberrant cytokine production. Mutations in Janus Kinase-2 (JAK2), calreticulin (CALR) and myeloproliferative leukemia protein (MPL) genes have been recently associated to MF and they all activate the JAK/STAT signaling pathway. Since this pathway is essential in shaping the immune response, we investigated the role of circulating immune subsets and cytokines in 38 patients (20 carrying JAK2(V617F),13 exon-9 CALR mutation and 5 triple negative). In comparison to healthy donors, patients presented a reduced amount of circulating dendritic cells (DCs) associated with a defective ability of monocytes in differentiating into DCs. In addition, we found a reduction in circulating T-helper (Th)1 and Th17 and hypo-functional innate lymphoid cells (ILC). Results analyzed according to the mutational status showed that patients carrying JAK2(V617F) mutation had a reduction in Th17, myeloid-DCs and effector Tregs as well as increased ILC1 and cytokine producing Tregs. The CALR mutated patients revealed high ILC3 levels, reduced Th1 and their monocytes had a reduced capacity to mature in vitro into fully committed DCs. Their Tregs were also less effective in inhibiting the proliferation of autologous effector T-cells due to an increased proliferative status induced by CALR mutation. Triple negative patients presented a reduced amount of total circulating CD3, effectors Tregs and Th1 with increased ILC1. Overall, we have demonstrated that in MF different mutations lead to phenotypic and functional alterations in different immune subsets that may have a potential role in disease progression and susceptibility to infections.

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