Pathogenesis of follicular lymphoma

Lackraj, Tracy; Goswami, Rashmi S.; Kridel, Robert

doi:10.1016/j.beha.2017.10.006

Cited by 46 publications

(31 citation statements)

References 168 publications

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“…For example, STAT3 is considered a key driver gene of large granular lymphocyte leukemia (LGL), and STAT3 mutations have been found in both NK cell -type and T celltype LGL [37]. Another study detected KMT2D mutations in patients with a variety of lymphoproliferative diseases [38][39][40], although the specific mechanism of action is still unclear. The other previously mentioned mutant genes have also been reported to be associated with various types of lymphoproliferative diseases or tumors [41][42][43][44][45][46], but no studies have detected mutations in these aforementioned genes in patients with HVLPD.…”

Section: Discussionmentioning

confidence: 99%

Hydroa vacciniforme-like lymphoproliferative disorder: A study of clinicopathology and whole-exome sequencing in Chinese patients

Xie

Wang

2020

Journal of Dermatological Science

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Background: Hydroa vacciniforme-like lymphoproliferative disorder (HVLPD) encompasses a rare group of Epstein-Barr virus (EBV)-associated lymphoproliferative diseases. Objective: To define the clinical and pathologic characteristics of HVLPD and to identify mutant genes that may be related to the development of HVLPD. Methods: Clinical data and archived formalin-fixed, paraffin-embedded tissue were obtained from 19 patients. Specimens were analyzed by immunohistochemistry and in situ hybridization to detect EBVencoded RNA (EBER1/2) and for T cell receptor (TCR) gene rearrangements. Whole-exome sequencing (WES) analysis was also performed in this study. Results: Thirteen patients survived between 3-58 months (median, 21 months) during the follow-up. Six patients who were almost adults (>15 years old) and died of the disease presented with facial edema. Lactate dehydrogenase (LDH) levels were elevated, and the TCR gene rearrangement test was positive more frequently in the patients who died. Compared with Chinese patients in a similar previous report, our patients had significantly higher proliferation (in all cases, the Ki-67 index was greater than 10 %) and a more aggressive clinical course. Moreover, after WES and Sanger verification, STAT3, IKBKB, ELF3, CHD7, KMT2D, ELK1, RARB and HPGDS were screened out in our patients. Conclusions: HVLPD refers to a heterogeneous group of cutaneous lymphoproliferative diseases with different clinical and pathological features that affect patient outcomes. Gene mutations may be correlated with the development of HVLPD, and our study may provide new therapeutic targets for HVLPD.

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Section: Discussionmentioning

confidence: 99%

Hydroa vacciniforme-like lymphoproliferative disorder: A study of clinicopathology and whole-exome sequencing in Chinese patients

Xie

Wang

2020

Journal of Dermatological Science

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“…The pathogenesis of follicular lymphoma (FL), the most common indolent B-cell non-Hodgkin lymphoma characterized by the presence of t (14;18) and BCL-2 overexpression, is thought to be the result of a close collaboration between recurrent somatic mutations and a permissive microenvironment. 1,2 FL tumor cells are dependent on their microenvironment for proliferation and survival, remaining dependent on signals through the B-cell receptor (BCR). 3 In this context, 2 populations present in the tumor niche are fundamental: follicular dendritic cells (FDCs) and dendritic cellspecific intercellular adhesion molecule-3-grabbing nonintegrinexpressing macrophages (Mf).…”

Section: Introductionmentioning

confidence: 99%

PI3Kδ inhibition reshapes follicular lymphoma–immune microenvironment cross talk and unleashes the activity of venetoclax

et al. 2020

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Despite idelalisib approval in relapsed follicular lymphoma (FL), a complete characterization of the immunomodulatory consequences of phosphatidylinositol 3-kinase δ (PI3Kδ) inhibition, biomarkers of response, and potential combinatorial therapies in FL remain to be established. Using ex vivo cocultures of FL patient biopsies and follicular dendritic cells (FDCs) to mimic the germinal center (n = 42), we uncovered that PI3Kδ inhibition interferes with FDC-induced genes related to angiogenesis, extracellular matrix formation, and transendothelial migration in a subset of FL samples, defining an 18-gene signature fingerprint of idelalisib sensitivity. A common hallmark of idelalisib found in all FL cases was its interference with the CD40/CD40L pathway and induced proliferation, together with the downregulation of proteins crucial for B–T-cell synapses, leading to an inefficient cross talk between FL cells and the supportive T-follicular helper cells (TFH). Moreover, idelalisib downmodulates the chemokine CCL22, hampering the recruitment of TFH and immunosupressive T-regulatory cells to the FL niche, leading to a less supportive and tolerogenic immune microenvironment. Finally, using BH3 profiling, we uncovered that FL–FDC and FL–macrophage cocultures augment tumor addiction to BCL-XL and MCL-1 or BFL-1, respectively, limiting the cytotoxic activity of the BCL-2 inhibitor venetoclax. Idelalisib restored FL dependence on BCL-2 and venetoclax activity. In summary, idelalisib exhibits a patient-dependent activity toward angiogenesis and lymphoma dissemination. In all FL cases, idelalisib exerts a general reshaping of the FL immune microenvironment and restores dependence on BCL-2, predisposing FL to cell death, providing a mechanistic rationale for investigating the combination of PI3Kδ inhibitors and venetoclax in clinical trials.

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“…FL can be classified according to the WHO into grade I-III categories based on histological features that correlate with clinical outcome. Several large studies have identified numerous recurrent mutations affecting the B-cell receptor signaling and differentiation, cell cycle regulation, derangements of epigenetic modification and immune evasion that can be linked to clinical progression of the disease [22][23][24][25], however the mechanism of clonal evolution is still a matter of debate [26,27]. The IgV H somatic hypermutation based spatial evolution of follicular lymphoma have been demonstrated previously [28,29].…”

Section: Discussionmentioning

confidence: 99%

Grade I, II and III Follicular Lymphomas Express Ig VH Genes with Different Patterns of Somatic Mutation

Csernus

Tímár

Fülöp

et al. 2020

Pathol. Oncol. Res.

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Follicular lymphoma (FL) is an indolent, B-cell, non-Hodgkin's lymphoma with varying cytological appearance and clinical behavior. The genetic hallmark of FL is the t(14;18) translocation, and as a germinal center derived entity it is also characterized by somatic hypermutation of the immunoglobulin heavy chain (IgH) gene. In an attempt to correlate this molecular signature with the cytological grading of FL, we have analyzed the IgH variable (IgV H), regions in all cytological grades of FL. Four FL cases showing t(14;18) translocation were classified into grade I-III categories according to the current WHO guidelines. The IgV H gene segments were PCR-amplified, sequenced, and compared to their respective germline IgV H sequences. The neoplastic cells of grade I and II FLs revealed clonally related, but highly divergent IgV H gene sequences indicating the ongoing nature of somatic hypermutation. Grade III FL also showed extensive presence of somatic hypermutation, but these mutations were not associated with intraclonal divergence. Thus, these results suggest that grade I-II and grade III FL may represent different biological entities. The presence of ongoing somatic hypermutation of IgV H sequences in grade I and II FLs is compatible with direct follicular origin of these tumor cells, contrasting the homogenous, stable clones of grade III FL resembling a post-follicular stage of B-cell development. Our findings demonstrate that contrary to the three tiered cytological grading, molecular features of IgH genes classify FL into two distinct subcategories. These studies also suggest that with progression FL gains post-follicularlike molecular features and becomes independent of the germinal center microenvironment.

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Pathogenesis of follicular lymphoma

Cited by 46 publications

References 168 publications

Hydroa vacciniforme-like lymphoproliferative disorder: A study of clinicopathology and whole-exome sequencing in Chinese patients

Hydroa vacciniforme-like lymphoproliferative disorder: A study of clinicopathology and whole-exome sequencing in Chinese patients

PI3Kδ inhibition reshapes follicular lymphoma–immune microenvironment cross talk and unleashes the activity of venetoclax

Grade I, II and III Follicular Lymphomas Express Ig VH Genes with Different Patterns of Somatic Mutation

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