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:10.1080/2162402X.2017.1345402

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

36 Citations (Scopus)

Abstract

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.

Original language	English
Article number	e1345402
Journal	OncoImmunology
Volume	6
Issue number	10
Early online date	11 Aug 2017
DOIs	https://doi.org/10.1080/2162402X.2017.1345402
Publication status	Published - 3 Oct 2017

Keywords

Calreticulin
chronic inflammation
Immune dysregulation
JAK2
Myelofibrosis

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1080/2162402X.2017.1345402

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Romano, M., Sollazzo, D., Trabanelli, S., Barone, M., Polverelli, N., Perricone, M., Forte, D., Luatti, S., Cavo, M., Vianelli, N., Jandus, C., Palandri, F., & Catani, L. (2017). Mutations in JAK2 and Calreticulin genes are associated with specific alterations of the immune system in myelofibrosis. OncoImmunology, 6(10), Article e1345402. https://doi.org/10.1080/2162402X.2017.1345402

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

abstract = "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.",

keywords = "Calreticulin, chronic inflammation, Immune dysregulation, JAK2, Myelofibrosis",

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

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doi = "10.1080/2162402X.2017.1345402",

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Romano, M, Sollazzo, D, Trabanelli, S, Barone, M, Polverelli, N, Perricone, M, Forte, D, Luatti, S, Cavo, M, Vianelli, N, Jandus, C, Palandri, F & Catani, L 2017, 'Mutations in JAK2 and Calreticulin genes are associated with specific alterations of the immune system in myelofibrosis', OncoImmunology, vol. 6, no. 10, e1345402. https://doi.org/10.1080/2162402X.2017.1345402

TY - JOUR

T1 - Mutations in JAK2 and Calreticulin genes are associated with specific alterations of the immune system in myelofibrosis

AU - Romano, Marco

AU - Sollazzo, Daria

AU - Trabanelli, Sara

AU - Barone, Martina

AU - Polverelli, Nicola

AU - Perricone, Margherita

AU - Forte, Dorian

AU - Luatti, Simona

AU - Cavo, Michele

AU - Vianelli, Nicola

AU - Jandus, Camilla

AU - Palandri, Francesca

AU - Catani, Lucia

PY - 2017/10/3

Y1 - 2017/10/3

N2 - 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.

AB - 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.

KW - Calreticulin

KW - chronic inflammation

KW - Immune dysregulation

KW - JAK2

KW - Myelofibrosis

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DO - 10.1080/2162402X.2017.1345402

M3 - Article

AN - SCOPUS:85027367006

SN - 2162-4011

VL - 6

JO - OncoImmunology

JF - OncoImmunology

IS - 10

M1 - e1345402

ER -

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

Abstract

Keywords

UN SDGs

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