ALK-Negative Anaplastic Large Cell Lymphoma (ALCL): Prognostic Implications of Molecular Subtyping and JAK-STAT Pathway

Abstract

The anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a clinically distinct but heterogeneous entity and lacks the specific immunophenotypic or genetic features compared with the ALK-positive ALCL. Recent molecular studies have provided genetic landscapes of ALK-negative ALCL that have prognostic significance. In this study, we subtyped ALK-negative ALCL based on DUSP22 rearrangements and TP63 expression and also looked for mutations in JAK-STAT pathway. The subtyping of the ALK-negative ALCL in relation to DUSP22 rearrangement and TP63 expression was done using fluorescence in situ hybridization and immunohistochemistry, respectively. The hotspot JAK-STAT mutations were analyzed using Sanger sequencing and amplification refractory mutation system polymerase chain reaction (PCR) and Signal transducer and activator of transcription 3 (STAT3) expression by immunohistochemistry. Forty-eight cases of ALCL were included with median age of 30 years and sex ratio of 1.8:1. The p63 expression was detected in 26.7% of ALK-negative ALCL cases. DUSP22 rearrangement was noted in 12.5% cases of p63-negative ALK-negative ALCLs. DUSP22 rearranged cases had better overall survival in contrast to p63 expressing and triple negative ALCLs. Triple negative ALCLs showed inferior overall survival rate. STAT3 expression was evident in 61.1% and 60% of ALK-positive and ALK-negative ALCLs, respectively. None of the cases subjected to Sanger sequencing as well as amplification refractory mutation system PCR for hotspot mutation analysis of JAK1 (exon 24) and STAT3 (exon 21) revealed any mutation. ALK-negative ALCL is a genetically heterogeneous disease with widely disparate clinical outcomes. Subtyping of ALK-negative ALCL based on DUSP22 rearrangement and p63 expression provides prognostic information.

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

“…We found that p-STAT3 was expressed in 22 of 45 (48.8%) ALK − ALCL cases, whereas JAK1/3 and/or STAT3 mutations were only detected in 4 of 21 (19%) ALK − ALCL cases. These results support previous observations that various mechanisms can lead to the activation of the JAK/STAT3 signaling pathway in ALK − ALCL cases, and it is not restricted to JAK and/or STAT3 mutations 6,12. Interestingly, we observed that 1 p-STAT3 + case harbored loss-of-function mutations in the gene encoding SOCS1 protein.…”

“…These results support previous observations that various mechanisms can lead to the activation of the JAK/ STAT3 signaling pathway in ALK − ALCL cases, and it is not restricted to JAK and/or STAT3 mutations. 6,12 Interestingly, we observed that 1 p-STAT3 + case harbored loss-of-function mutations in the gene encoding SOCS1 protein. This protein negatively regulates STAT3 signal transduction in ALK − ALCLs and a mutation in the gene may contribute to constitutive STAT3 phosphorylation.…”

<i>DUSP22</i> rearrangement is associated with a distinctive immunophenotype but not outcome in patients with systemic ALK-negative anaplastic large cell lymphoma

“…DUSP22 rearrangement has been reported most often in cases of systemic ALK-negative ALCL and primary cutaneous ALCL, occasionally in lymphomatoid papulosis and rarely in peripheral T cell lymphoma, NOS, but not in ALK+ ALCL [23,24]. DUSP22 rearrangement occurs in 13-30% of ALK-negative ALCL cases [6,[8][9][10][11]. Consistent with prior reports, 27% of systemic ALK-negative ALCL cases in the present study harbored DUSP22 rearrangement.…”

“…ALK-negative ALCL is a genetically heterogeneous entity, with 13-30% of cases harboring DUSP22 rearrangement (R) and 2-8% of cases carrying TP63-R [6,[8][9][10][11]. TP63 and DUSP22 rearrangements are nearly mutually exclusive.…”

A Ferroptosis Molecular Subtype-Related Signature for Predicting Prognosis and Response to Chemotherapy in Patients with Chronic Lymphocytic Leukemia

“…TP63 contributes to maintaining redox homeostasis through glutathione biogenesis, utilization, and regeneration. TP63 is a prognostic gene in breast cancer patients [ 26 ], lung squamous cell carcinoma [ 27 ], pancreatic cancer [ 28 ], skin cutaneous melanoma [ 29 ], anaplastic lymphoma kinase-negative anaplastic large cell lymphoma [ 30 ], etc. STEAP3 is a metal reductase, encoding a transmembrane protein that functions as an iron transporter and coordinates the regulation of iron homeostasis [ 31 ].…”