New responsibilities for aged kinases in B‐lymphomas

Abstract

The knowledge accumulated over the last decade on B-cell-derived non-Hodgkin lymphoma (B-NHL) pathogenesis has led to the identification of several molecular abnormalities, opening new perspectives in the design of novel therapies. Indeed, drugs targeting specific biochemical pathways critical for B-NHL cell survival, proliferation, and fitness within the malignant microenvironment are now available to the clinician: the B-cell receptor signaling inhibitors of BTK, PI3Kδ, ζ, γ, and SYK or the pro-apoptotic BH3-mimetics are clear examples of it. Moreover, it is emerging that malignant B-cell growth is sustained not only by mutations in oncogenes/tumor suppressors but also by the "addiction" to nononcogene (ie, nonstructurally altered) molecules. In this regard, a consistent body of data has established that the Ser/Thr kinases CK1, CK2, and GSK3 are involved in malignant lymphocyte biology and act as pro-survival and signaling-boosting molecules, both in precursor and mature B-cell tumors. Currently, an experimental and clinical groundwork is available, upon which to design CK1-, CK2-, and GSK3-directed antilymphoma/leukemia therapies. In this review, we have examined the main features of CK1, CK2, and GSK3 kinases, summarized the data in B-NHL supporting them as suitable therapeutic targets, and proposed a perspective on potential future research development. K E Y W O R D S B lymphocytes, CK1, CK2, GSK3, lymphoma, protein kinase 1 | EVOLVING PARADIGMS IN NON-HODGKIN LYMPHOMAS Non-Hodgkin lymphomas (NHL) are collectively the most frequent hematologic cancer, among the top 10 most frequent malignant tumors worldwide. 1 B-cell-derived NHL (B-NHL) are by far more frequent than T-cell-derived NHL, and between them, tumors arising from the mature B cell are more frequent. The 2016 World Health Organization (WHO) classification of NHL has recognized approximately 60 distinct entities. 2 In the group of B-NHL, diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype, accounting for 35% of all B-NHL, followed by follicular lymphoma (FL), which accounts for up to 20% to 25% of B-NHL. These two B-NHL subtypes originate from germinal center (GC) centrocytes/centroblasts. 3 However, a proportion of DLBCL are from post-GC origin, the so called "activated B-cell" (ABC)-type DLBCL. Patients affected by this latter subtype are believed to be subjected to a more dismal prognosis as compared with those with GC B-cell (GCB) type. 4 Other less frequent B-NHL are mantle cell lymphoma (MCL, approximately 10% of all B-NHL), marginal zone lymphoma (MZL, about 5% of all B-NHL), small lymphocyte lymphoma/chronic lymphocytic leukemia (SLL/CLL, 5%), lymphoplasmacytic lymphoma (LPL, 3%). 2 Deep sequencing of the genome and the transcriptome has provided a great amount of data describing mutations and aberrant expression of cell signaling molecules. For instance, the molecular classification of DLBCL has been progressively refined from the seminal paper of Alizadeh describing the GCB/ABC/undetermined subtypes, 4 based on gene expres...

<p>Lights and Shade of Next-Generation Pi3k Inhibitors in Chronic Lymphocytic Leukemia</p>

“…22 Upon growth factors stimulation, active PI3K generates PIP3 which recruits AKT through the pleckstrin homology domain of the latter, thereby inducing full activation of AKT through its phosphorylation at Thr308 by PDK1 and at Ser473 by mTORC2, thus fully activating AKT. Activated AKT phosphorylates GSK3, 23,24 inhibiting it, TSC2, caspase 9 and PRAS40 promoting proliferation, differentiation, apoptosis, angiogenesis and metabolism.…”

From pathogenesis to personalized treatments of neuropathies in hematological malignancies

“…The BCR signaling pathway plays a major role in B‐cells survival and proliferation, and in the oncogenesis of B‐NHL (Figure 1). After antigen recognition by the BCR, the Bruton's tyrosine kinase (BTK) is activated leading to the proteasomal degradation of IkB (inhibitor of NF‐kB) which subsequently modulates NF‐kB and downstream proteins 3 . Consequently, the development of BTK inhibitors, such as ibrutinib, provided durable response in clinical trial and became standard of treatment in most relapsed B‐NHL.…”

“…Phosphorylation of IκB proteins leads to its ubiquitylation and proteasomal degradation, thereby the release of the NF‐κB subunits. Subsequently, the NF‐κB subunits, RELA (p65)‐p50 in the classical pathway and RELB‐p52 in the alternative pathway, migrate to the nucleus where they bind to specific DNA‐binding sites and induce the expression of genes involved in B‐cell proliferation and survival 3 . BCR signaling.…”

“…On the other hand, Gβ/Gγ dimer can trigger PI3K, regulating cell migration, but also PLC which catalyzes the hydrolysis of phosphatidylinositol 4,5‐bisphosphate (PIP2) into inositol 1,4,5‐trisphosphate (IP3) and diacylglycerol. IP3 production results in Ca2+ mobilization from the intracellular smooth reticula, while diacylglycerol promotes the activation of protein kinase C (PKC) and MAPK kinases 3 …”

“…Moreover, increased insight into the biology of plasma cells‐derived diseases have helped the understanding of specific treatments mechanism. For example, immunomodulating drugs, such as thalidomide, lenalidomide and pomalidomide, target cereblon, which is part of an E3 ubiquitin ligase complex that causes ubiquitylation and subsequent proteasomal degradation of some transcription factors like ikaros, aiolos and casein kinase 1 3 . In addition, proteasome inhibition by bortezomib or carfilzomib leads to the accumulation of IkB protein, the inhibitor of NF‐kB triggering plasma cells apoptosis and impinging the production as well as the secretion of cytokines such as IL‐6 and vascular endothelial growth factor (VEGF) by stromal cells 33 …”