STAT3 dysregulation in mature T and NK cell lymphomas

TY - JOUR

T1 - STAT3 dysregulation in mature T and NK cell lymphomas

AU - Seffens, Angelina

AU - Herrera, Alberto

AU - Tegla, Cosmin

AU - Buus, Terkild B.

AU - Hymes, Kenneth B.

AU - Ødum, Niels

AU - Geskin, Larisa J.

AU - Koralov, Sergei B.

PY - 2019

Y1 - 2019

N2 - T cell lymphomas comprise a distinct class of non-‐-Hodgkin’s lymphomas, which include mature T and natural killer (NK) cell neoplasms. While each malignancy within this group is characterized by unique clinicopathologic features, dysregulation in the Janus tyrosine family of kinases/Signal transducer and activator of transcription (JAK/STAT) signaling pathway, specifically aberrant STAT3 activation, is a common feature among these lymphomas. The mechanisms driving dysregulation vary among T cell lymphoma subtypes and include activating mutations in upstream kinases or STAT3 itself, formation of oncogenic kinases which drive STAT3 activation, loss of negative regulators of STAT3, and the induction of a pro-‐-tumorigenic inflammatory microenvironment. Constitutive STAT3 activation has been associated with the expression of targets able to increase pro-‐-survival signals and provide malignant fitness. Patients with dysregulated STAT3 signaling tend to have inferior clinical outcomes, which underscores the importance of STAT3 signaling in malignant progression. Targeting of STAT3 has shown promising results in preclinical studies in T cell lymphoma lines, ex-‐-vivo primary malignant patient cells, and in mouse models of disease. However, targeting this pleotropic pathway in patients has proven difficult. Here we review the recent contributions to our understanding of the role of STAT3 in T cell lymphomagenesis, mechanisms driving STAT3 activation in T cell lymphomas, and current efforts at targeting STAT3 signaling in T cell malignancies.

AB - T cell lymphomas comprise a distinct class of non-‐-Hodgkin’s lymphomas, which include mature T and natural killer (NK) cell neoplasms. While each malignancy within this group is characterized by unique clinicopathologic features, dysregulation in the Janus tyrosine family of kinases/Signal transducer and activator of transcription (JAK/STAT) signaling pathway, specifically aberrant STAT3 activation, is a common feature among these lymphomas. The mechanisms driving dysregulation vary among T cell lymphoma subtypes and include activating mutations in upstream kinases or STAT3 itself, formation of oncogenic kinases which drive STAT3 activation, loss of negative regulators of STAT3, and the induction of a pro-‐-tumorigenic inflammatory microenvironment. Constitutive STAT3 activation has been associated with the expression of targets able to increase pro-‐-survival signals and provide malignant fitness. Patients with dysregulated STAT3 signaling tend to have inferior clinical outcomes, which underscores the importance of STAT3 signaling in malignant progression. Targeting of STAT3 has shown promising results in preclinical studies in T cell lymphoma lines, ex-‐-vivo primary malignant patient cells, and in mouse models of disease. However, targeting this pleotropic pathway in patients has proven difficult. Here we review the recent contributions to our understanding of the role of STAT3 in T cell lymphomagenesis, mechanisms driving STAT3 activation in T cell lymphomas, and current efforts at targeting STAT3 signaling in T cell malignancies.

KW - JAK/STAT

KW - Lymphomagenesis

KW - STAT3

KW - T cell lymphoma

U2 - 10.3390/cancers11111711

DO - 10.3390/cancers11111711

M3 - Review

C2 - 31684088

AN - SCOPUS:85074651065

SN - 2072-6694

VL - 11

JO - Cancers

JF - Cancers

IS - 11

M1 - 1711

ER -