Correction. "The 5th edition of The World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms" Leukemia. 2022 Jul;36(7):1720-1748

We herein present an overview of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4th edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5th edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as well as inclusion of tumour-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms

The role of c-Jun N-terminal Kinase (JNK) in the pathobiology of the anaplastic large cell lymphoma

Anaplastic large-cell lymphoma (ALCL) frequently carries the t(2;5)(p23;q35), resulting in aberrant expression of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). We show that in 293T and Jurkat cells, forced expression of active NPM-ALK, but not kinase-dead mutant NPM-ALK (210K>R), induced JNK and cJun phosphorylation, and this was linked to a dramatic increase in AP-1 transcriptional activity. Conversely, inhibition of ALK activity in NPM-ALK(+) ALCL cells resulted in a concentration-dependent dephosphorylation of JNK and cJun and decreased AP-1 DNA-binding. In addition, JNK physically binds NPM-ALK and is highly activated in cultured and primary NPM-ALK(+) ALCL cells. C-Jun phosphorylation in NPM-ALK(+) ALCL cells is mediated by JNKs, as shown by selective knocking down of JNK1 and JNK2 genes using siRNA. Inhibition of JNK activity using SP600125 decreased cJun phosphorylation and AP-1 transcriptional activity and this was associated with decreased cell proliferation and G2/M cell-cycle arrest in a dose-dependent manner. Silencing of the c-Jun gene by siRNA led to a decreased S-phase cell-cycle fraction associated with upregulation of p21 and downregulation of cyclin D3 and cyclin A. Taken together, these findings reveal a novel function of NPM-ALK, phosphorylation and activation of JNK and c-Jun, which may contribute to uncontrolled cell-cycle progression and oncogenesis.Το (ALK+) αναπλαστικό λέμφωμα από μεγάλα κύτταρα (ΑΛΜΚ) (anaplastic large cells lymphoma, ALCL) πολύ συχνά φέρει την χρωμοσωμική μετατόπιση t(2;5) που οδηγεί στην υπερέκφραση και ενεργοποίηση της ογκοπρωτείνης NPM-ALK. Στη παρούσα μελέτη, δείχνουμε ότι σε 293Τ και Jurkat κύτταρα η εξωγενής έκφραση της ενεργού NPM-ALK κινάσης, σε αντίθεση με την μεταλλαγμένη/μη ενεργή NPM-ALK πρωτεΐνη (210K>R), οδήγησε σε ενεργοποίηση/φωσφορυλίωση της κινάσης JNK και του cJun, γεγονός το οποίο αποδεικνύεται από την παρουσία αυξημένης ενεργότητας πρόσδεσης των μεταγραφικών παραγόντων AP-1. Ταυτόχρονα, αναστολή της δράσης της ALK κινάσης σε NPM-ALK(+) ALCL κυτταρικές σειρές με τη χρήση ειδικού αναστολέα, είχε ως αποτέλεσμα τη μείωση των επιπέδων φωσφορυλίωσης των JNK και cJun πρωτεϊνών και τη μείωση της δράσης του AP-1 μεταγραφικού παράγοντα στη δημιουργία DNA- AP-1 συμπλεγμάτων. Δείχνουμε, επίσης, σε αυτή τη μελέτη ότι σε NPM-ALK(+) ALCL ιστούς και κυτταρικές σειρές η JNK κινάση είναι φωσφορυλιωμένη σε υψηλά επίπεδα. In vitro μελέτες σε NPM-ALK(+) ALCL κυτταρικές σειρές δείχνουν ότι η JNK πρωτεΐνη αποτελεί μέρος του συμπλέγματος της NPM-ALK με αποτέλεσμα την άμεση/έμμεση ενεργοποίησή της από την NPM-ALK. Επίσης, αποσιώπηση του γονιδίου JNK1 και JNK2 με την χορήγηση ειδικού siRNA συσχετίστηκε με σημαντική μείωση των επιπέδων της φωσφορυλιωμένης και ολικής μορφής της c-Jun πρωτεΐνης, αποδεικνύοντας έτσι τον ρόλο της JNK στην ενεργοποίηση του c-Jun στο ALK(+) ALCL λέμφωμα. Φαρμακολογική αναστολή της δράσης της JNK κινάσης με τη χρήση ειδικού αναστολέα, SP600125, είχε παρόμοια αποτελέσματα και επίσης συσχετίστηκε με μείωση του κυτταρικού πολλαπλασιασμού και αναστολή του κυτταρικού κύκλου στην φάση G2/M. Αποσιώπηση του γονιδίου cJun συνοδεύτηκε από μείωση της φάσης S του κυτταρικού κύκλου και από μείωση των κυκλινών A, D2 και D3 και αύξηση στα επίπεδα του αναστολέων των κυκλινο-εξαρτώμενων κινασών (CDKI’s), συμπεριλαμβανομένου του p21. Συνολικά, τα ευρήματα μας δείχνουν μια επιπλέον σημαντική ογκογόνο δράση της NPM-ALK κινάσης, τη φωσφορυλίωση/ενεργοποίηση της JNK και του μεταγραφικού παράγοντα c-Jun, η οποία μπορεί να έχει ογκογόνες ιδιότητες μέσω ρύθμισης του κυτταρικού κύκλου και επιβίωσης των κυττάρων του ALK(+) ALCL

AP-1 Transcription Factors as Regulators of Immune Responses in Cancer

Immune check point blockade therapy has revolutionized the standard of cancer treatment and is credited with producing remarkable tumor remissions and increase in overall survival. This unprecedented clinical success however is feasible for a limited number of cancer patients due to resistance occurring before or during a course of immunotherapy, which is often associated with activation of oncogenic signaling pathways, co-inhibitory checkpoints upregulation or expansion of immunosuppressive regulatory T-cells (Tregs) in the tumor microenviroment (TME). Targeted therapy aiming to inactivate a signaling pathway such as the Mitogen Activated Protein Kinases (MAPKs) has recently received a lot of attention due to emerging data from preclinical studies indicating synergy with immune checkpoint blockade therapy. The dimeric transcription factor complex Activator Protein-1 (AP-1) is a group of proteins involved in a wide array of cell processes and a critical regulator of nuclear gene expression during T-cell activation. It is also one of the downstream targets of the MAPK signaling cascade. In this review, we will attempt to unravel the roles of AP-1 in the regulation of anti-tumor immune responses, with a focus on the regulation of immune checkpoints and Tregs, seeking to extract useful insights for more efficacious immunotherapy

Extracavitary/solid variant of primary effusion lymphoma

Primary effusion lymphoma (PEL) is a distinct clinicopathologic entity associated with human herpesvirus 8 (HHV8) infection that mostly affects patients with immunodeficiency. Primary effusion lymphoma usually presents as a malignant effusion involving the pleural, peritoneal, and/or pericardial cavities without a tumor mass. Rare cases of HHV8-positive lymphoma with features similar to PEL can present as tumor masses in the absence of cavity effusions and are considered to represent an extracavitary or solid variant of PEL. Here, we report 3 cases of extracavitary PEL arising in human immunodeficiency virus–infected men. Two patients had lymphadenopathy and underwent lymph node biopsy. One patient had a mass involving the ileum and ascending colon. In lymph nodes, the tumor was predominantly sinusoidal. The tumor involving the ileum and ascending colon presented as 2 masses, 12.5 × 10.6 × 2.6 cm in the colon and 3.6 × 2.7 × 1.9 cm in the ileum. In each case, the neoplasms were composed of large anaplastic cells, and 2 cases had “hallmark cells.” Immunohistochemistry showed that all cases were positive for HHV8 and CD138. One case also expressed CD4 and CD30, and 1 case was positive for Epstein-Barr virus–encoded RNA. Evidence of B-cell differentiation was poorly developed in all tumors. These cases highlight the importance of assessing HHV8 in an anaplastic tumor that arises in a human immunodeficiency virus–positive patient and further contributes to the limited literature currently available for extracavitary PEL

Indolent peripheral T-cell lymphoma involving the gastrointestinal tract

We describe an unusual case of indolent peripheral T-cell lymphoma with multifocal involvement of the gastrointestinal tract. The patient, a 42-year-old Asian man, has been followed up for more than 10 years without chemotherapy and multiple gastrointestinal biopsies showing similar findings. Histologically, the neoplasm expanded into the lamina propria and/or focally extended into the submucosa and was composed of small- to medium-sized lymphocytes with slightly irregular nuclear contours and clear cytoplasm and rare large lymphocytes. The tumor cells were positive for CD3, CD8, granzyme B, and TIA-1 (subset) and negative for CD5, CD56, and Epstein-Barr virus-encoded RNA. Molecular studies for T-cell receptor γ and/or β chain gene rearrangement demonstrated the same clone at different sites and times during the course of the disease. Rare cases of indolent peripheral T-cell lymphoma of the gastrointestinal tract have been previously described and need to be further characterized to avoid the use of aggressive chemotherapy

Activation of mammalian target of rapamycin signaling pathway contributes to tumor cell survival in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma

Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) frequently carries the t(2;5)(p23;q35) resulting in aberrant expression of chimeric nucleophosmin-ALK. Previously, nucleophosmin-ALK has been shown to activate phosphatidylinositol 3-kinase (PI3K) and its downstream effector, the serine/threonine kinase AKT. In this study, we hypothesized that the mammalian target of rapamycin (mTOR) pathway, which functions downstream of AKT, mediates the oncogenic effects of activated PI3K/AKT in ALK+ ALCL. Here, we provide evidence that mTOR signaling phosphoproteins, including mTOR, eukaryotic initiation factor 4E-binding protein-1, p70S6K, and ribosomal protein S6, are highly phosphorylated in ALK+ ALCL cell lines and tumors. We also show that AKT activation contributes to mTOR phosphorylation, at least in part, as forced expression of constitutively active AKT by myristoylated AKT adenovirus results in increased phosphorylation of mTOR and its downstream effectors. Conversely, inhibition of AKT expression or activity results in decreased mTOR phosphorylation. In addition, pharmacologic inhibition of PI3K/AKT down-regulates the activation of the mTOR signaling pathway. We also show that inhibition of mTOR with rapamycin, as well as silencing mTOR gene product expression using mTOR-specific small interfering RNA, decreased phosphorylation of mTOR signaling proteins and induced cell cycle arrest and apoptosis in ALK+ ALCL cells. Cell cycle arrest was associated with modulation of G(1)-S-phase regulators, including the cyclin-dependent kinase inhibitors p21(waf1) and p27(kip1). Apoptosis following inhibition of mTOR expression or function was associated with down-regulation of antiapoptotic proteins, including c-FLIP, MCL-1, and BCL-2. These findings suggest that the mTOR pathway contributes to nucleophosmin-ALK/PI3K/AKT-mediated tumorigenesis and that inhibition of mTOR represents a potential therapeutic strategy in ALK+ ALCL