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JAK3/STAT3 oncogenic pathway and PRDM1 expression stratify clinicopathologic features of extranodal NK/T‑cell

Jumei Liu¹, Li Liang¹, Dong Li¹

¹Department of Pathology, Peking University First Hospital, Beijing 100034, P.R. China.

Oncology Reports

|April 20, 2019

Abstract:

The inactivation of tumor suppressor gene positive regulatory domain containing I (PRDM1) and activation of signal transducer and activator of transcription 3 (STAT3) have been detected in the majority of extranodal NK/T‑cell lymphoma, nasal type (EN‑NK/T‑NT) cases. In the present study, their association with and effects on the clinicopathologic features of EN‑NK/T‑NT are described. PRDM1 was revealed to be expressed in 19 out of 58 patients (32.8%) with EN‑NK/T‑NT, and phosphorylated STAT3 was overexpressed in 42 out of 58 (72.4%). Oncogenic pathways were investigated by NanoString encounter technology in 5 PRDM1(+) and 5 PRDM1(‑) EN‑NK/T‑NT specimens. Multiple oncogenic pathways involved in cell apoptosis, cellcycle (CC) and angiogenesis were discriminately activated in EN‑NK/T‑NT cases, and in PRDM1(+) cases in particular. The sustained activation of the Janus kinase 3 (JAK)/STAT3 pathway was more pronounced. In addition, missense mutations in the SRC homology 2 domain of STAT3 were detected in 7 out of 37 EN‑NK/T‑NT cases (18.92%), and the acquired mutation was related to the activation of the JAK3/STAT3 pathway. The downregulation of PRDM1 and upregulation of phospho‑STAT3 (Tyr705) were associated with angiocentric infiltration of EN‑NK/T‑NT (P=0.039). Notably, the prognosis of patients in the PRDM1(+)/STAT3 [mutated (mut‑)] group was considerably improved than that of patients in the STAT3(mut+)/PRDM(‑) group (P=0.037). In addition, the inhibition of NK/T cell lymphoma cell lines by Stattic and tofacitinib could suppress cell proliferation by inducing cell apoptosis or arresting the CC. The present results revealed that the JAK3/STAT3 oncogenic pathway and PRDM1 expression could stratify clinicopathologic features of EN‑NK/T‑NT. The inhibition of the JAK3/STAT3 pathway may serve as a treatment option for EN‑NK/T‑NT.

Insights

In extranodal NK/T-cell lymphoma, nasal type (EN‑NK/T‑NT), PRDM1 inactivation and STAT3 activation are common. Targeting the JAK3/STAT3 pathway may offer a new treatment strategy for EN‑NK/T‑NT.

Area of Science:

Oncology
Molecular Biology
Immunology

Background:

Extranodal NK/T-cell lymphoma, nasal type (EN‑NK/T‑NT) frequently exhibits PRDM1 gene inactivation and STAT3 pathway activation.
These molecular alterations are implicated in the pathogenesis and progression of EN‑NK/T‑NT.

Purpose of the Study:

To investigate the association between PRDM1 expression, STAT3 activation, and clinicopathologic features in EN‑NK/T‑NT.
To explore the role of oncogenic pathways, including JAK3/STAT3, in EN‑NK/T‑NT.
To evaluate the therapeutic potential of targeting the JAK3/STAT3 pathway.

Main Methods:

Analysis of PRDM1 expression and phosphorylated STAT3 (p-STAT3) in EN‑NK/T‑NT patient samples.
NanoString nCounter technology to investigate oncogenic pathways in PRDM1-positive and PRDM1-negative specimens.
Detection of STAT3 mutations using sequencing.
In vitro studies using Stattic and tofacitinib to inhibit JAK3/STAT3 signaling in lymphoma cell lines.

Main Results:

PRDM1 was expressed in 32.8% and p-STAT3 overexpressed in 72.4% of EN‑NK/T‑NT cases.
Multiple oncogenic pathways, particularly JAK3/STAT3, were activated in EN‑NK/T‑NT, with pronounced activation in PRDM1-positive cases.
STAT3 mutations were found in 18.92% of cases and correlated with JAK3/STAT3 pathway activation.
Downregulation of PRDM1 and upregulation of p-STAT3 were associated with angiocentric infiltration (P=0.039).
Patients with PRDM1 positivity and wild-type STAT3 had a better prognosis than those with PRDM1 negativity and mutated STAT3 (P=0.037).
Inhibition of JAK3/STAT3 signaling suppressed lymphoma cell proliferation by inducing apoptosis and cell cycle arrest.

Conclusions:

PRDM1 expression and JAK3/STAT3 pathway activation are significant factors that can stratify clinicopathologic features and prognosis in EN‑NK/T‑NT.
Targeting the JAK3/STAT3 pathway represents a promising therapeutic strategy for EN‑NK/T‑NT.

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