Pervasive mutations of JAK-STAT pathway genes in classical Hodgkin lymphoma

Enrico Tiacci, Erik Ladewig, Gianluca Schiavoni, Alex Penson, Elisabetta Fortini, Valentina Pettirossi, Yuchun Wang, Ariele Rosseto, Alessandra Venanzi, Sofija Vlasevska, Roberta Pacini, Simonetta Piattoni, Alessia Tabarrini, Alessandra Pucciarini, Barbara Bigerna, Alessia Santi, Alessandro M Gianni, Simonetta Viviani, Antonello Cabras, Stefano AscaniBarbara Crescenzi, Cristina Mecucci, Laura Pasqualucci, Raul Rabadan, Brunangelo Falini

Research output: Contribution to journalArticle

Abstract

Dissecting the pathogenesis of classical Hodgkin lymphoma (cHL), a common cancer in young adults, remains challenging because of the rarity of tumor cells in involved tissues (usually <5%). Here, we analyzed the coding genome of cHL by microdissecting tumor and normal cells from 34 patient biopsies for a total of ∼50 000 singly isolated lymphoma cells. We uncovered several recurrently mutated genes, namely, STAT6 (32% of cases), GNA13 (24%), XPO1 (18%), and ITPKB (16%), and document the functional role of mutant STAT6 in sustaining tumor cell viability. Mutations of STAT6 genetically and functionally cooperated with disruption of SOCS1, a JAK-STAT pathway inhibitor, to promote cHL growth. Overall, 87% of cases showed dysregulation of the JAK-STAT pathway by genetic alterations in multiple genes (also including STAT3, STAT5B, JAK1, JAK2, and PTPN1), attesting to the pivotal role of this pathway in cHL pathogenesis and highlighting its potential as a new therapeutic target in this disease.

Original languageEnglish
Pages (from-to)2454-2465
Number of pages12
JournalBlood
Volume131
Issue number22
DOIs
Publication statusPublished - May 31 2018

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Hodgkin Disease
Mutation
Genes
Neoplasms
Young Adult
Lymphoma
Cell Survival
Genome
Biopsy
Growth
Therapeutics

Cite this

Tiacci, E., Ladewig, E., Schiavoni, G., Penson, A., Fortini, E., Pettirossi, V., ... Falini, B. (2018). Pervasive mutations of JAK-STAT pathway genes in classical Hodgkin lymphoma. Blood, 131(22), 2454-2465. https://doi.org/10.1182/blood-2017-11-814913

Pervasive mutations of JAK-STAT pathway genes in classical Hodgkin lymphoma. / Tiacci, Enrico; Ladewig, Erik; Schiavoni, Gianluca; Penson, Alex; Fortini, Elisabetta; Pettirossi, Valentina; Wang, Yuchun; Rosseto, Ariele; Venanzi, Alessandra; Vlasevska, Sofija; Pacini, Roberta; Piattoni, Simonetta; Tabarrini, Alessia; Pucciarini, Alessandra; Bigerna, Barbara; Santi, Alessia; Gianni, Alessandro M; Viviani, Simonetta; Cabras, Antonello; Ascani, Stefano; Crescenzi, Barbara; Mecucci, Cristina; Pasqualucci, Laura; Rabadan, Raul; Falini, Brunangelo.

In: Blood, Vol. 131, No. 22, 31.05.2018, p. 2454-2465.

Research output: Contribution to journalArticle

Tiacci, E, Ladewig, E, Schiavoni, G, Penson, A, Fortini, E, Pettirossi, V, Wang, Y, Rosseto, A, Venanzi, A, Vlasevska, S, Pacini, R, Piattoni, S, Tabarrini, A, Pucciarini, A, Bigerna, B, Santi, A, Gianni, AM, Viviani, S, Cabras, A, Ascani, S, Crescenzi, B, Mecucci, C, Pasqualucci, L, Rabadan, R & Falini, B 2018, 'Pervasive mutations of JAK-STAT pathway genes in classical Hodgkin lymphoma', Blood, vol. 131, no. 22, pp. 2454-2465. https://doi.org/10.1182/blood-2017-11-814913
Tiacci E, Ladewig E, Schiavoni G, Penson A, Fortini E, Pettirossi V et al. Pervasive mutations of JAK-STAT pathway genes in classical Hodgkin lymphoma. Blood. 2018 May 31;131(22):2454-2465. https://doi.org/10.1182/blood-2017-11-814913
Tiacci, Enrico ; Ladewig, Erik ; Schiavoni, Gianluca ; Penson, Alex ; Fortini, Elisabetta ; Pettirossi, Valentina ; Wang, Yuchun ; Rosseto, Ariele ; Venanzi, Alessandra ; Vlasevska, Sofija ; Pacini, Roberta ; Piattoni, Simonetta ; Tabarrini, Alessia ; Pucciarini, Alessandra ; Bigerna, Barbara ; Santi, Alessia ; Gianni, Alessandro M ; Viviani, Simonetta ; Cabras, Antonello ; Ascani, Stefano ; Crescenzi, Barbara ; Mecucci, Cristina ; Pasqualucci, Laura ; Rabadan, Raul ; Falini, Brunangelo. / Pervasive mutations of JAK-STAT pathway genes in classical Hodgkin lymphoma. In: Blood. 2018 ; Vol. 131, No. 22. pp. 2454-2465.
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abstract = "Dissecting the pathogenesis of classical Hodgkin lymphoma (cHL), a common cancer in young adults, remains challenging because of the rarity of tumor cells in involved tissues (usually <5{\%}). Here, we analyzed the coding genome of cHL by microdissecting tumor and normal cells from 34 patient biopsies for a total of ∼50 000 singly isolated lymphoma cells. We uncovered several recurrently mutated genes, namely, STAT6 (32{\%} of cases), GNA13 (24{\%}), XPO1 (18{\%}), and ITPKB (16{\%}), and document the functional role of mutant STAT6 in sustaining tumor cell viability. Mutations of STAT6 genetically and functionally cooperated with disruption of SOCS1, a JAK-STAT pathway inhibitor, to promote cHL growth. Overall, 87{\%} of cases showed dysregulation of the JAK-STAT pathway by genetic alterations in multiple genes (also including STAT3, STAT5B, JAK1, JAK2, and PTPN1), attesting to the pivotal role of this pathway in cHL pathogenesis and highlighting its potential as a new therapeutic target in this disease.",
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AU - Fortini, Elisabetta

AU - Pettirossi, Valentina

AU - Wang, Yuchun

AU - Rosseto, Ariele

AU - Venanzi, Alessandra

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AU - Tabarrini, Alessia

AU - Pucciarini, Alessandra

AU - Bigerna, Barbara

AU - Santi, Alessia

AU - Gianni, Alessandro M

AU - Viviani, Simonetta

AU - Cabras, Antonello

AU - Ascani, Stefano

AU - Crescenzi, Barbara

AU - Mecucci, Cristina

AU - Pasqualucci, Laura

AU - Rabadan, Raul

AU - Falini, Brunangelo

N1 - © 2018 by The American Society of Hematology.

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N2 - Dissecting the pathogenesis of classical Hodgkin lymphoma (cHL), a common cancer in young adults, remains challenging because of the rarity of tumor cells in involved tissues (usually <5%). Here, we analyzed the coding genome of cHL by microdissecting tumor and normal cells from 34 patient biopsies for a total of ∼50 000 singly isolated lymphoma cells. We uncovered several recurrently mutated genes, namely, STAT6 (32% of cases), GNA13 (24%), XPO1 (18%), and ITPKB (16%), and document the functional role of mutant STAT6 in sustaining tumor cell viability. Mutations of STAT6 genetically and functionally cooperated with disruption of SOCS1, a JAK-STAT pathway inhibitor, to promote cHL growth. Overall, 87% of cases showed dysregulation of the JAK-STAT pathway by genetic alterations in multiple genes (also including STAT3, STAT5B, JAK1, JAK2, and PTPN1), attesting to the pivotal role of this pathway in cHL pathogenesis and highlighting its potential as a new therapeutic target in this disease.

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