STAT3 Dysregulation in Mature T and NK Cell Lymphomas

Abstract

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 pre-clinical 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.

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

“…T/NK-NHL is a heterogeneous group of malignancies often associated with poor clinical outcomes, and each malignancy within this group is characterized by unique clinicopathologic features, while T cell receptor/NF/kB (TCR/NF/kB) signaling highly enriched and dysregulation of JAK/STAT pathway, specifically aberrant STAT3 activation, are the common feature among these lymphomas [324][325][326]. A study with 426 adult T cell leukemia/lymphoma (ATL) cases associated with human T cell leukemia virus type-1 (HTLV-1) infection shows that PI3KCD mutation is also observed in 9 of 370 (2.4%) cases besides the highly enriched for TCR/NF/kB signaling, T cell trafficking and other T cell-related pathways [324].…”

The NKL-code for innate lymphoid cells reveals deregulated expression of NKL homeobox genes HHEX and HLX in anaplastic large cell lymphoma (ALCL)

“…ALCLs lacking the fusion gene NPM1-ALK possess activating mutations of STAT3 instead, highlighting the role of aberrant STAT3 activity in this malignancy [23]. However, deregulated and mutated STAT3 is not restricted to ALCL and plays an oncogenic role in other types of T-and NK-cell lymphomas as well [24,25]. Aberrant activities of AP1 TFs including JUN, JUNB and BATF3 are an additional ALCL hallmark [26].…”

“…Activating mutations of STAT3 have been frequently detected in NK-and T-cell lymphomas including ALKnegative ALCL [24,25]. Inactivating mutations of MGA are present in T-cell and NK-cell lymphoma patients which carry no STAT3 mutation [25], suggesting complementary effects of these genes.…”

MicroRNAs in the Pathogenesis, Diagnosis, Prognosis and Targeted Treatment of Cutaneous T-Cell Lymphomas

“…Indeed, ectopic overexpression of miR-337 suppressed key aspects of CTCL such as viability and invasion. The tumor-suppressive properties were induced through direct repression of STAT3 activity, essential for CTCL tumorigenesis [11,87]. Other findings suggest that miR-150 is an important player in CTCL tumor invasion.…”

“…Abnormalities of certain molecular pathways are frequently observed in CTCL and are believed to play an important role in a subset of patients [7]. Recurrent mutations include genetic abnormalities that facilitate constitutive activation of JAK/STAT signaling as well as oncogenic mutations that potentiate constitutive NFκB signaling [8][9][10][11][12][13]. Recently, several lines of evidence have pointed towards a key role for epigenetic dysregulation in the pathogenesis of CTCL [14][15][16].…”