Primary cytotoxic T-cell lymphomas harbor recurrent targetable alterations in the JAK-STAT pathway

While normal B- and T-lymphocytes require antigenic ligands to become activated via their B- and T-cell receptors (BCR and TCR, respectively), B- and T-cell lymphomas show the broad spectrum of cell activation mechanisms regarding their dependence on BCR or TCR signaling, including loss of such dependence. These mechanisms are generally better understood and characterized for B-cell than for T-cell lymphomas. While some lymphomas, particularly the indolent, low-grade ones remain antigen-driven, other retain dependence on activation of their antigen receptors seemingly in an antigen-independent manner with activating mutations of the receptors playing a role. A large group of lymphomas, however, displays complete antigen receptor independence, which can develop gradually, in a stepwise manner or abruptly, through involvement of powerful oncogenes. Whereas some of the lymphomas undergo activating mutations of genes encoding proteins involved in signaling cascades downstream of the antigen-receptors, others employ activation mechanisms capable of substituting for these BCR- or TCR-dependent signaling pathways, including reliance on signaling pathways physiologically activated by cytokines. Finally, lymphomas can develop cell-lineage infidelity and in the extreme cases drastically rewire their cell activation mechanisms and engage receptors and signaling pathways physiologically active in hematopoietic stem cells or non-lymphoid cells. Such profound reprograming may involve partial cell dedifferentiation or transdifferentiation towards histocytes, dendritic, or mesodermal cells with various degree of cell maturation along these lineages. In this review, we elaborate on these diverse pathogenic mechanisms underlying cell plasticity and signaling reprogramming as well as discuss the related diagnostic and therapeutic implications and challenges.

Section: Malignant Transformation Of T Lymphocytes Driven By Other Po...mentioning

confidence: 99%

Diverse and reprogrammable mechanisms of malignant cell transformation in lymphocytes: pathogenetic insights and translational implications

Wasik,

Kim,

Nejati

2024

“…JAK/STAT signaling plays a prominent role in adult T-cell leukemia and lymphoma because of the effects of HTLV1 lymphomagenesis ( 34 ), T-large granular leukemia ( 35 ), T-lymphoblastic leukemia/lymphoma ( 35 ), cutaneous lymphomas ( 36 , 37 ), and various nodal and extranodal TCLS ( 38 ). Notably, STAT3 is the main downstream effector of ALK in ALCL ( 22 ).…”

Section: Jak/stat Signaling In Ptclsmentioning

confidence: 99%

Tyrosine kinases in nodal peripheral T-cell lymphomas

Piccaluga

Cascianelli²,

Inghirami

2023

Nodal peripheral T-cell lymphomas (PTCL) are uncommon and heterogeneous tumors characterized by a dismal prognosis. Targeted therapy has been proposed. However, reliable targets are mostly represented by a few surface antigens (e.g., CD52 and CD30), chemokine receptors (e.g., CCR4), and epigenetic gene expression regulation. In the last two decades, however, several studies have supported the idea that tyrosine kinase (TK) deregulation might be relevant for both the pathogenesis and treatment of PTCL. Indeed, they can be expressed or activated as a consequence of their involvement in genetic lesions, such as translocations, or by ligand overexpression. The most striking example is ALK in anaplastic large-cell lymphomas (ALCL). ALK activity is necessary to support cell proliferation and survival, and its inhibition leads to cell death. Notably, STAT3 was found to be the main downstream ALK effector. Other TKs are consistently expressed and active in PTCLs, such as PDGFRA, and members of the T-cell receptor signaling family, such as SYK. Notably, as in the case of ALK, STAT proteins have emerged as key downstream factors for most of the involved TK.

“…However, a deeper understanding of the genomic landscape could provide insight into potential therapeutic approaches especially in early stage disease ( 76 ). Stratification of individual patients according to mutational profile/deregulated pathway could allow the use of existing treatments such as Ipilimumab ( CD28-CTLA4 fusion), Ruxolitinib and Tofacitinib ( JAK mutations or JAK2 fusions as detected in rare aggressive cytotoxic CTCL variants) ( 77 , 78 ) and Bortezomib (NFkB pathway) ( 79 ). Patients with abnormalities of epigenetic regulation such as DNMT3A and TET2 could be selected for treatment with demethylating agents such as 5-Azactidine and/or HDACi, whilst those with RHOA mutations could be eligible for PI3K inhibitors (Duvelisib).…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Advances in the understanding and treatment of Cutaneous T-cell Lymphoma

Bakr

Whittaker

2022

Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of non-Hodgkin’s lymphomas (NHL) characterised by the clonal proliferation of malignant, skin homing T-cells. Recent advances have been made in understanding the molecular pathogenesis of CTCL. Multiple deep sequencing studies have revealed a complex genomic landscape with large numbers of novel single nucleotide variants (SNVs) and copy number variations (CNVs). Commonly perturbed genes include those involved in T-cell receptor signalling, T-cell proliferation, differentiation and survival, epigenetic regulators as well as genes involved in genome maintenance and DNA repair. In addition, studies in CTCL have identified a dominant UV mutational signature in contrast to systemic T-cell lymphomas and this likely contributes to the high tumour mutational burden. As current treatment options for advanced stages of CTCL are associated with short-lived responses, targeting these deregulated pathways could provide novel therapeutic approaches for patients. In this review article we summarise the key pathways disrupted in CTCL and discuss the potential therapeutic implications of these findings.