Molecular pathogenesis of germinal center‐derived B cell lymphomas

Pasqualucci, Laura

doi:10.1111/imr.12745

Cited by 64 publications

(76 citation statements)

References 199 publications

(479 reference statements)

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“…Nevertheless, this translocation, which allows the overexpression of the anti-apoptotic molecule BCL2, could be detected at low frequency within recirculating post-GC memory B cells of most healthy individuals, indicating that it is not sufficient to trigger overt FL [ 4 ]. Advances in high-throughput genetic analyses have revealed the complex landscape of additional molecular events that support FL development [ 5 , 6 , 7 ]. Of note, beyond the well-accepted identification of FL B cells as centrocytes that fail to differentiate [ 8 ], recent single-cell transcriptomic analyses revealed a desynchronization of the GC-specific gene expression program in FL malignant cells that might adopt new dynamic modes of functional diversity [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Integrative Analysis of Cell Crosstalk within Follicular Lymphoma Cell Niche: Towards a Definition of the FL Supportive Synapse

Pangault

Amé-Thomas

Rossille

et al. 2020

Cancers

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Follicular lymphoma (FL), the most frequent indolent non-Hodgkin’s B cell lymphoma, is considered as a prototypical centrocyte-derived lymphoma, dependent on a specific microenvironment mimicking the normal germinal center (GC). In agreement, several FL genetic alterations affect the crosstalk between malignant B cells and surrounding cells, including stromal cells and follicular helper T cells (Tfh). In our study, we sought to deconvolute this complex FL supportive synapse by comparing the transcriptomic profiles of GC B cells, Tfh, and stromal cells, isolated from normal versus FL tissues, in order to identify tumor-specific pathways. In particular, we highlighted a high expression of IL-6 and IL-7 in FL B cells that could favor the activation of FL Tfh overexpressing IFNG, able in turn to stimulate FL B cells without triggering MHC (major histocompatibility) class II expression. Moreover, the glycoprotein clusterin was found up-regulated in FL stromal cells and could promote FL B cell adhesion. Finally, besides its expression on Tfh, CD200 was found overexpressed on tumor B cells and could contribute to the induction of the immunosuppressive enzyme indoleamine-2,3 dioxygenase by CD200R-expressing dendritic cells. Altogether our findings led us to outline the contribution of major signals provided by the FL microenvironment and their interactions with malignant FL B cells.

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Section: Introductionmentioning

confidence: 99%

Integrative Analysis of Cell Crosstalk within Follicular Lymphoma Cell Niche: Towards a Definition of the FL Supportive Synapse

Pangault

Amé-Thomas

Rossille

et al. 2020

Cancers

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“…For instance, the molecular classification of DLBCL has been progressively refined from the seminal paper of Alizadeh describing the GCB/ABC/undetermined subtypes, based on gene expression, to the latest categorization into molecular subgroups, subdividing DLBCL also according to the spectrum of genetic alterations displayed . Also, for FL, the genetic profiling has identified frequent recurrent mutations, such as those affecting the H3K27 methyltransferase EZH2, the chromatin regulator gene CREBBP and KMT2D (MLL2) . In the case of MCL, the genomic analysis has identified recurrent mutations affecting TP53, ATM, CCND1, MLL2, and NOTCH1 and NOTCH2 genes .…”

Section: Evolving Paradigms In Non‐hodgkin Lymphomasmentioning

confidence: 99%

“…Cell signaling pathways are critical in B‐NHL pathophysiology . B‐NHL cells are, in most instances, dependent on constitutively active cascades that transmit survival and proliferation inputs from the surface membrane to the nucleus, where transcriptional and epigenetic processes translate the signals in effective outputs, like cell cycle progression, apoptosis inhibition, and invasiveness . On the basis of this, aberrant signal transduction is genetic and epigenetic mechanisms as well as the origination of an abnormal tumor microenvironment.…”

Section: Signaling In Nhlmentioning

confidence: 99%

New responsibilities for aged kinases in B‐lymphomas

Manni

Arjomand

Visentin

et al. 2019

Hematological Oncology

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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...

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“…2,3 The genetic hallmark of FL is the t(14;18) chromosomal translocation that constitutively activates the anti-apoptotic gene BCL2, along with recurrent mutations of histone modifier genes. 1 Additional genetic mutations affecting various biological pathways have been identified by genomic analyses, 1,4 including aberrations in components of the cellular nutrient-sensing pathway. Specifically, a sizable subset of FL cases show missense mutations in the nucleotide binding domain of the gene encoding the RagC GTPase (RRAGC).…”

Section: Takedownmentioning

confidence: 99%