STAT3 and TP53 mutations associate with poor prognosis in anaplastic large cell lymphoma

Cutaneous and breast implant-associated anaplastic large-cell lymphomas (cALCLs and BI-ALCLs) are two localized forms of peripheral T-cell lymphomas (PTCLs) that are recognized as distinct entities within the family of ALCL. JAK-STAT signaling is a common feature of all ALCL subtypes, whereas DUSP22/IRF4, TP63 and TYK gene rearrangements have been reported in a proportion of ALK-negative sALCLs and cALCLs. Both cALCLs and BI-ALCLs differ in their gene expression profiles compared to PTCLs; however, a direct comparison of the genomic alterations and transcriptomes of these two entities is lacking. By performing RNA sequencing of 1385 genes (TruSight RNA Pan-Cancer, Illumina) in 12 cALCLs, 10 BI-ALCLs and two anaplastic lymphoma kinase (ALK)-positive sALCLs, we identified the previously reported TYK2-NPM1 fusion in 1 cALCL (1/12, 8%), and four new intrachromosomal gene fusions in 2 BI-ALCLs (2/10, 20%) involving genes on chromosome 1 (EPS15-GNG12 and ARNT-GOLPH3L) and on chromosome 17 (MYO18A-GIT1 and NF1-GOSR1). One of the two BI-ALCL samples showed a complex karyotype, raising the possibility that genomic instability may be responsible for intra-chromosomal fusions in BI-ALCL. Moreover, transcriptional analysis revealed similar upregulation of the PI3K/Akt pathway, associated with enrichment in the expression of neurotrophin signaling genes, which was more conspicuous in BI-ALCL, as well as differences, i.e., over-expression of genes involved in the RNA polymerase II transcription program in BI-ALCL and of the RNA splicing/processing program in cALCL.

Section: Discussionmentioning

confidence: 99%

RNA Sequencing of Primary Cutaneous and Breast-Implant Associated Anaplastic Large Cell Lymphomas Reveals Infrequent Fusion Transcripts and Upregulation of PI3K/AKT Signaling via Neurotrophin Pathway Genes

Napoli

Vacca

Bertolazzi

et al. 2021

“…A recent multi-institutional study using deep targeted next generation sequencing of 47 ALK+ and 35 ALK- ALCLs has identified that ALK- ALCLs have an average of 4.2 mutations per patient, whereas ALK+ cases have an average of 2.6 mutations per patient [ 67 ]. Mutated genes predictive of a poor prognosis (defined as death of disease, refractory to therapy, and/or relapsed disease) independent of ALK status included TP53 , STAT3 , EPHA5 , JAK1 , PRDM1 , LRP1B , and KMT2D.…”

Section: Systemic Alk- Alclmentioning

confidence: 99%

“…Mutated genes predictive of a poor prognosis (defined as death of disease, refractory to therapy, and/or relapsed disease) independent of ALK status included TP53 , STAT3 , EPHA5 , JAK1 , PRDM1 , LRP1B , and KMT2D. From all these, the STAT3 and JAK1 mutations were identified in 26% of ALK- ALCLs and the STAT3 and TP53 mutations had shorter overall survivals [ 67 ]. Similarly, the expression of p53 and beta-catenin, and the co-expression of these markers at the protein level has been observed more in association with ALK- ALCL than with ALK+ ALCL and it appears to correlate with a poor prognosis [ 68 ].…”

Section: Systemic Alk- Alclmentioning

confidence: 99%

“…DUPS22 and TP63 gene rearrangements are absent in ALK+ ALCL but can be found in a subset of PTCL, NOS, and therefore, they support but do not confirm the diagnosis of ALK- ALCL and should be interpreted in the right context [ 53 ]. The prognostic impact of these rearrangements is also likely affected by the presence/absence of STAT3 and TP53 mutations, as recently shown by a next generation sequencing study in a large cohort of patients with ALCL [ 67 ].…”

Section: Systemic Alk- Alclmentioning

confidence: 99%

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ALK-Negative Anaplastic Large Cell Lymphoma: Current Concepts and Molecular Pathogenesis of a Heterogeneous Group of Large T-Cell Lymphomas

Piña‐Oviedo

Ortíz-Hidalgo

Carballo-Zarate

et al. 2021

Anaplastic large cell lymphoma (ALCL) is a subtype of CD30+ large T-cell lymphoma (TCL) that comprises ~2% of all adult non-Hodgkin lymphomas. Based on the presence/absence of the rearrangement and expression of anaplastic lymphoma kinase (ALK), ALCL is divided into ALK+ and ALK-, and both differ clinically and prognostically. This review focuses on the historical points, clinical features, histopathology, differential diagnosis, and relevant cytogenetic and molecular alterations of ALK- ALCL and its subtypes: systemic, primary cutaneous (pc-ALCL), and breast implant-associated (BIA-ALCL). Recent studies have identified recurrent genetic alterations in this TCL. In systemic ALK- ALCL, rearrangements in DUSP22 and TP63 are detected in 30% and 8% of cases, respectively, while the remaining cases are negative for these rearrangements. A similar distribution of these rearrangements is seen in pc-ALCL, whereas none have been detected in BIA-ALCL. Additionally, systemic ALK- ALCL—apart from DUSP22-rearranged cases—harbors JAK1 and/or STAT3 mutations that result in the activation of the JAK/STAT signaling pathway. The JAK1/3 and STAT3 mutations have also been identified in BIA-ALCL but not in pc-ALCL. Although the pathogenesis of these alterations is not fully understood, most of them have prognostic value and open the door to the use of potential targeted therapies for this subtype of TCL.

“…Excessive STAT3 phosphorylation due to PTPN6 loss is related to shorter overall survival (OS) durations [10]. In ALK-negative cell lines, STAT3 and JAK1 are the most commonly mutated, both of which are associated with an adverse effect on survival [43]. Both ALK-negative ALCLs and ALK-positive ALCLs have a high expression of BATF3 and TMOD1 and low expression of TCR signaling-related genes, including CD3ε, ZAP70, LAT, and SLP76 [7,40].…”

Section: Anaplastic Large Cell Lymphomamentioning

confidence: 99%

Emerging Therapeutic Landscape of Peripheral T-Cell Lymphomas Based on Advances in Biology: Current Status and Future Directions

Khan

Samaniego

Hagemeister

et al. 2021

T-cell lymphomas are a relatively rare group of malignancies with a diverse range of pathologic features and clinical behaviors. Recent molecular studies have revealed a wide array of different mechanisms that drive the development of these malignancies and may be associated with resistance to therapies. Although widely accepted chemotherapeutic agents and combinations, including stem cell transplantation, obtain responses as initial therapy for these diseases, most patients will develop a relapse, and the median survival is only 5 years. Most patients with relapsed disease succumb within 2 to 3 years. Since 2006, the USFDA has approved five medications for treatment of these diseases, and only anti-CD30-therapy has made a change in these statistics. Clearly, newer agents are needed for treatment of these disorders, and investigators have proposed studies that evaluate agents that target these malignancies and the microenvironment depending upon the molecular mechanisms thought to underlie their pathogenesis. In this review, we discuss the currently known molecular mechanisms driving the development and persistence of these cancers and discuss novel targets for therapy of these diseases and agents that may improve outcomes for these patients.