JAK/STAT3 Signaling Activation Related to Distinct Clinicopathologic Features in Systemic ALK− Anaplastic Large Cell Lymphomas

Abstract

Systemic anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a group of heterogenous CD30 + T-cell non-Hodgkin lymphomas. Previous studies have highlighted the importance of JAK/STAT3 signaling activation in the molecular pathogenesis of ALK − ALCLs. In the present study, we aimed to establish a potential relationship between JAK/STAT3 signaling activation and clinicopathologic features in ALK − ALCLs, and further recognize the heterogenous nature of these neoplasms. Immunohistochemistry staining of the phosphorylated-STAT3 (p-STAT3) and dualspecificity protein phosphatase 22 (DUSP22) gene rearrangement analysis were performed. Forty-five cases of ALK − ALCL were divided into 3 groups, including 9 DUSP22-rearranged ALCLs, 21 p-STAT3 + double-negative (DN) ALCLs (both ALK and DUSP22 rearrangement negative), and 15 p-STAT3 − DN-ALCLs. Morphologically, p-STAT3 + DN-ALCLs exhibited sheet-like neoplastic cells and sometimes showed large pleomorphic cells scattered in a lymphocyte-rich background more frequently than those in other ALK − ALCLs subtypes. Phenotypically, the p-STAT3 + DN-ALCLs frequently expressed cytotoxic molecules, epithelial membrane antigen, and programmed death-ligand 1, whereas CD3 and CD5 expression was not observed. Clinically, patients with p-STAT3 + DN-ALCLs had a better prognosis than those with p-STAT3 − DN-ALCLs. These observations suggest that p-STAT3 + DN-ALCLs represent a distinct subtype of ALK − ALCLs. Identifying ALK − ALCL subtypes by using p-STAT3 staining and DUSP22 rearrangement is a promising approach that may contribute to risk stratification and better treatment decisions in the future clinical practice.

Phosphorylated STAT3 as a potential diagnostic and predictive biomarker in ALK- ALCL vs. CD30high PTCL, NOS

“…In ALK + ALCL, ALK kinase constitutively drives STAT3 phosphorylation ( 30 ). However, in ALK - ALCL, only ~20% of ALK- ALCLs have activate mutations of JAK1 and/or STAT3 genes ( 9 ), which could not explain the high rate of pSTAT3 positivity both in our study and other researchers’ work ( 17 , 18 , 32 ). Additionally, compared with ALK +/- ALCL, a lower proportion of PTCL, NOS expresses pSTAT3, reported also by other researchers ( 14 , 18 ).…”

DUSP22 Ameliorates Endothelial-to-Mesenchymal Transition in HUVECs through Smad2/3 and MAPK Signaling Pathways

“…(3) DUSP22 participates in inflammatory diseases and reduces the production of inflammatory cytokines [20,45,46]. (4) DUSP22 inhibits the STAT3 signal pathway activated by IL-6 [35,46]. (5) DUSP22 dephosphorylates FAK and supports cell migration [47].…”

“…DUSP22 is an atypical PTP consisting of 184 amino acid residues that is widely expressed in a variety of human tissues. DUSP22, also known as c-JUN N-terminal kinase (JNK) pathway-associated phosphatase (JKAP), dephosphorylates P38/mitogen-activated protein kinase (MAPK) [30], JNK/MAPK [31], estrogen receptor (ER) [32], focal adhesion kinases (FAK) [33], lymphocyte-specific protein tyrosine kinase [34], and signal transducer and activator of transcription 3 (STAT3) [35] and regulates T-cell receptor signaling [36]. Hence, DUSP22 plays a key role in controlling multiple signaling pathways.…”