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Biological hallmarks of splenic marginal zone lymphoma (SMZL) remain poorly described. Herein, we performed in-depth SMZL characterization through multimodal single-cell analyses of paired blood/spleen samples. The 3'-single-cell RNA-sequencing, Cellular Indexing of Transcriptomes and Epitopes by sequencing, and 5'-V(D)J single-cell RNA-sequencing datasets were integrated to characterize SMZL transcriptome profiles, including B-cell receptor and T-cell receptor repertoires. Hyperexpanded B-cell clones in the spleen were at a memory-like stage, whereas recirculating tumor B-cells in blood encompassed multiple differentiation stages, indicating an unexpected desynchronization of the B-cell maturation program in SMZL cells. Spatial transcriptomics showed the enrichment of T-effector and T-follicular helper (TFH) signatures in the nodular subtype of SMZL. This latter also exhibited gene-based cell-cell interactions suggestive of dynamic crosstalk between TFH and cancer cells in transcriptomics, further substantiated by using imaging mass cytometry. Our findings provide a comprehensive high-resolution description of SMZL biological hallmarks and characterize, for the first time in situ, inter- and intra-patient heterogeneity at both transcriptomic and protein levels. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Linfoma de Células B de la Zona Marginal , Análisis de la Célula Individual , Neoplasias del Bazo , Transcriptoma , Humanos , Neoplasias del Bazo/genética , Neoplasias del Bazo/patología , Neoplasias del Bazo/metabolismo , Linfoma de Células B de la Zona Marginal/genética , Linfoma de Células B de la Zona Marginal/patología , Linfoma de Células B de la Zona Marginal/metabolismo , Linfoma de Células B de la Zona Marginal/inmunología , Perfilación de la Expresión Génica/métodos , Masculino , Femenino , Persona de Mediana Edad , Linfocitos B/patología , Linfocitos B/metabolismo , Anciano , Bazo/patología , Bazo/inmunología , Bazo/metabolismoRESUMEN
The assessment of chemotherapy response in osteosarcoma (OS), based on the average percentage of viable cells, is limited as it overlooks the spatial heterogeneity of tumor cell response (foci of resistant cells), immune microenvironment and bone microarchitecture. Despite the resulting positive classification for response to chemotherapy, some patients experience early metastatic recurrence, demonstrating that our conventional tools for evaluating treatment response are insufficient. We studied the interactions between tumor cells, immune cells (lymphocytes, histiocytes, osteoclasts), and bone extracellular matrix (ECM) in 18 surgical resection samples of osteosarcoma using multiplex and conventional immunohistochemistry (CD8, CD163, CD68, SATB2), combined with multi-scale characterization approaches in territories of good and poor response (GRT/PRT) to treatment. GRT and PRT were defined as subregions with <10% and ≥10% of viable tumor cells, respectively. Local correlations between bone ECM porosity and density of immune cells were assessed in these territories. Immune cell density was then correlated to overall patient survival. Two patterns were identified for histiocytes and osteoclasts. In poor responder (PR) patients, CD68 osteoclast density exceeded that of CD163 histiocytes, but was not related to bone ECM load. Conversely, in good responder (GR) patients, CD163 histiocytes were more numerous than CD68 osteoclasts. For both of them, a significant negative local correlation with bone ECM porosity was found (p<0,01). Moreover, in PRT, multinucleated osteoclasts were rounded and intermingled with tumor cells, whereas in GRT they were elongated and found in close contact with bone trabeculae. CD8 levels were always low in metastatic patients and those initially considered as GR but rapidly died from their disease. The specific recruitment of histiocytes and osteoclasts within the bone ECM, and the level of CD8 represent new features of osteosarcoma response to treatment. The associated prognostic signatures should be integrated into the therapeutic stratification algorithm of patients, after surgery.
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According to expert guidelines, lymph node surgical excision is the standard of care for lymphoma diagnosis. However, core needle biopsy (CNB) has become widely accepted as part of the lymphoma diagnostic workup over the past decades. The aim of this study was to present the largest multicenter inventory of lymph nodes sampled either by CNB or surgical excision in patients with suspected lymphoma and to compare their diagnostic performance in routine pathologic practice. We reviewed 32 285 cases registered in the French Lymphopath network, which provides a systematic expert review of all lymphoma diagnoses in France, and evaluated the percentage of CNB and surgical excision cases accurately diagnosed according to the World Health Organization classification. Although CNB provided a definitive diagnosis in 92.3% and seemed to be a reliable method of investigation for most patients with suspected lymphoma, it remained less conclusive than surgical excision, which provided a definitive diagnosis in 98.1%. Discordance rates between referral and expert diagnoses were higher on CNB (23.1%) than on surgical excision (21.2%; P = .004), and referral pathologists provided more cases with unclassified lymphoma or equivocal lesion through CNB. In such cases, expert review improved the diagnostic workup by classifying â¼90% of cases, with higher efficacy on surgical excision (93.3%) than CNB (81.4%; P < 10-6). Moreover, diagnostic concordance for reactive lesions was higher on surgical excision than CNB (P = .009). Overall, although CNB accurately diagnoses lymphoma in most instances, it increases the risk of erroneous or nondefinitive conclusions. This large-scale survey also emphasizes the need for systematic expert review in cases of lymphoma suspicion, especially in those sampled by using CNB.
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Neoplasias de la Mama , Linfoma , Humanos , Femenino , Biopsia con Aguja Gruesa/métodos , Linfoma/diagnóstico , Linfoma/cirugía , Linfoma/patología , Escisión del Ganglio Linfático , Ganglios Linfáticos/cirugía , Ganglios Linfáticos/patología , Biopsia , Estudios Retrospectivos , Neoplasias de la Mama/patología , Estudios Multicéntricos como AsuntoRESUMEN
Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.
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Neoplasias Hematológicas , Linfoma , Comités Consultivos , Consenso , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Humanos , Linfoma/patología , Organización Mundial de la SaludRESUMEN
The t(14;19)(q32;q13) often juxtaposes BCL3 with immunoglobulin heavy chain (IGH) resulting in overexpression of the gene. In contrast to other oncogenic translocations, BCL3 rearrangement (BCL3-R) has been associated with a broad spectrum of lymphoid neoplasms. Here we report an integrative whole-genome sequence, transcriptomic, and DNA methylation analysis of 13 lymphoid neoplasms with BCL3-R. The resolution of the breakpoints at single base-pair revealed that they occur in two clusters at 5' (n=9) and 3' (n=4) regions of BCL3 associated with two different biological and clinical entities. Both breakpoints were mediated by aberrant class switch recombination of the IGH locus. However, the 5' breakpoints (upstream) juxtaposed BCL3 next to an IGH enhancer leading to overexpression of the gene whereas the 3' breakpoints (downstream) positioned BCL3 outside the influence of the IGH and were not associated with its expression. Upstream BCL3-R tumors had unmutated IGHV, trisomy 12, and mutated genes frequently seen in chronic lymphocytic leukemia (CLL) but had an atypical CLL morphology, immunophenotype, DNA methylome, and expression profile that differ from conventional CLL. In contrast, downstream BCL3-R neoplasms were atypical splenic or nodal marginal zone lymphomas (MZL) with mutated IGHV, complex karyotypes and mutated genes typical of MZL. Two of the latter four tumors transformed to a large B-cell lymphoma. We designed a novel fluorescence in situ hybridization assay that recognizes the two different breakpoints and validated these findings in 17 independent tumors. Overall, upstream or downstream breakpoints of BCL3-R are mainly associated with two subtypes of lymphoid neoplasms with different (epi)genomic, expression, and clinicopathological features resembling atypical CLL and MZL, respectively.
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Leucemia Linfocítica Crónica de Células B , Linfoma de Células B Grandes Difuso , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Hibridación Fluorescente in Situ , Translocación Genética , Reordenamiento Génico , Linfoma de Células B Grandes Difuso/genética , Cadenas Pesadas de Inmunoglobulina/genética , Cromosomas Humanos Par 14/genéticaRESUMEN
The oncogenic events involved in breast implant-associated anaplastic large cell lymphoma (BI-ALCL) remain elusive. To clarify this point, we have characterized the genomic landscape of 34 BI-ALCLs (15 tumor and 19 in situ subtypes) collected from 54 BI-ALCL patients diagnosed through the French Lymphopath network. Whole-exome sequencing (n = 22, with paired tumor/germline DNA) and/or targeted deep sequencing (n = 24) showed recurrent mutations of epigenetic modifiers in 74% of cases, involving notably KMT2C (26%), KMT2D (9%), CHD2 (15%), and CREBBP (15%). KMT2D and KMT2C mutations correlated with a loss of H3K4 mono- and trimethylation by immunohistochemistry. Twenty cases (59%) showed mutations in ≥1 member of the JAK/STAT pathway, including STAT3 (38%), JAK1 (18%), and STAT5B (3%), and in negative regulators, including SOCS3 (6%), SOCS1 (3%), and PTPN1 (3%). These mutations were more frequent in tumor-type samples than in situ samples (P = .038). All BI-ALCLs expressed pSTAT3, regardless of the mutational status of genes in the JAK/STAT pathway. Mutations in the EOMES gene (12%) involved in lymphocyte development, PI3K-AKT/mTOR (6%), and loss-of-function mutations in TP53 (12%) were also identified. Copy-number aberration (CNA) analysis identified recurrent alterations, including gains on chromosomes 2, 9p, 12p, and 21 and losses on 4q, 8p, 15, 16, and 20. Regions of CNA encompassed genes involved in the JAK/STAT pathway and epigenetic regulators. Our results show that the BI-ALCL genomic landscape is characterized by not only JAK/STAT activating mutations but also loss-of-function alterations of epigenetic modifiers.
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Implantes de Mama/efectos adversos , Epigénesis Genética , Quinasas Janus/metabolismo , Linfoma Anaplásico de Células Grandes/etiología , Linfoma Anaplásico de Células Grandes/genética , Factores de Transcripción STAT/metabolismo , Transducción de Señal , Adulto , Anciano , Anciano de 80 o más Años , Variaciones en el Número de Copia de ADN , Femenino , Genoma Humano , Humanos , Linfoma Anaplásico de Células Grandes/patología , Persona de Mediana Edad , Mutación/genéticaRESUMEN
The class distribution of a training dataset is an important factor which influences the performance of a deep learning-based system. Understanding the optimal class distribution is therefore crucial when building a new training set which may be costly to annotate. This is the case for histological images used in cancer diagnosis where image annotation requires domain experts. In this paper, we tackle the problem of finding the optimal class distribution of a training set to be able to train an optimal model that detects cancer in histological images. We formulate several hypotheses which are then tested in scores of experiments with hundreds of trials. The experiments have been designed to account for both segmentation and classification frameworks with various class distributions in the training set, such as natural, balanced, over-represented cancer, and over-represented non-cancer. In the case of cancer detection, the experiments show several important results: (a) the natural class distribution produces more accurate results than the artificially generated balanced distribution; (b) the over-representation of non-cancer/negative classes (healthy tissue and/or background classes) compared to cancer/positive classes reduces the number of samples which are falsely predicted as cancer (false positive); (c) the least expensive to annotate non-ROI (non-region-of-interest) data can be useful in compensating for the performance loss in the system due to a shortage of expensive to annotate ROI data; (d) the multi-label examples are more useful than the single-label ones to train a segmentation model; and (e) when the classification model is tuned with a balanced validation set, it is less affected than the segmentation model by the class distribution of the training set.
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Aprendizaje Profundo , Neoplasias , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Neoplasias/diagnóstico por imagenRESUMEN
We previously reported a new form of light chain deposition disease (LCDD) presenting as diffuse cystic lung disorder that differs from the usual systemic form with respect to patient age, the male/female ratio, the involved organs, and the hematologic characteristics. We also demonstrated that the light chains were produced by an intrapulmonary B-cell clone and that this clone shared a stereotyped antigen receptor IGHV4-34/IGKV1. However, we only analyzed 3 patients. We conducted a retrospective study including lung tissue samples from 24 patients with pulmonary LCDD (pLCDD) matched with samples from 13 patients with pulmonary κ light chain amyloidosis (pAL amyloidosis) used as controls. Mass spectrometry-based proteomics identified immunoglobulin κ peptides as the main protein component of the tissue deposits in all patients. Interestingly, in pLCDD, IGKV1 was the most common κ family detected (86.4%), and IGKV1-8 was overrepresented compared with pAL amyloidosis (75% vs 11.1%, P = .0033). Furthermore, IGKV1-8 was predominantly associated with a diffuse cystic pattern (94%) in pLCDD. In conclusion, the high frequency of IGKV1-8 usage in cystic pLCDD constitutes an additional feature arguing for a specific entity distinct from the systemic form that preferentially uses IGKV4-1.
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Cadenas Ligeras de Inmunoglobulina/genética , Enfermedades Pulmonares/genética , Paraproteinemias/genética , Adulto , Femenino , Humanos , Enfermedades Pulmonares/patología , Masculino , Persona de Mediana Edad , Paraproteinemias/patología , Proteómica , Estudios RetrospectivosRESUMEN
PAX5 is a well-known haploinsufficient tumor suppressor gene in human B-cell precursor acute lymphoblastic leukemia (B-ALL) and is involved in various chromosomal translocations that fuse a part of PAX5 with other partners. However, the role of PAX5 fusion proteins in B-ALL initiation and transformation is ill-known. We previously reported a new recurrent t(7;9)(q11;p13) chromosomal translocation in human B-ALL that juxtaposed PAX5 to the coding sequence of elastin (ELN). To study the function of the resulting PAX5-ELN fusion protein in B-ALL development, we generated a knockin mouse model in which the PAX5-ELN transgene is expressed specifically in B cells. PAX5-ELN-expressing mice efficiently developed B-ALL with an incidence of 80%. Leukemic transformation was associated with recurrent secondary mutations on Ptpn11, Kras, Pax5, and Jak3 genes affecting key signaling pathways required for cell proliferation. Our functional studies demonstrate that PAX5-ELN affected B-cell development in vitro and in vivo featuring an aberrant expansion of the pro-B cell compartment at the preleukemic stage. Finally, our molecular and computational approaches identified PAX5-ELN-regulated gene candidates that establish the molecular bases of the preleukemic state to drive B-ALL initiation. Hence, our study provides a new in vivo model of human B-ALL and strongly implicates PAX5 fusion proteins as potent oncoproteins in leukemia development.
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Elastina/genética , Proteínas de Fusión Oncogénica/genética , Factor de Transcripción PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Animales , Linfocitos B/patología , Linfocitos B/fisiología , Elastina/metabolismo , Regulación Leucémica de la Expresión Génica , Técnicas de Sustitución del Gen , Janus Quinasa 3/genética , Ratones Transgénicos , Mutación , Neoplasias Experimentales , Proteínas de Fusión Oncogénica/metabolismo , Factor de Transcripción PAX5/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
MOTIVATION: Microsatellite instability (MSI) is a molecular marker of DNA mismatch repair deficiency frequently at play in oncogenesis. MSI testing is used for diagnostic, prognostic and therapeutic purposes in several cancers. The current gold standard analysis for microsatellite status is based on length distribution analysis of multiplex-PCR generated DNA fragments from tumor samples which is a laborious and time consuming method. Next generation sequencing (NGS) using amplicon panels is an easy, accurate and scalable technique to determine both the microsatellite status and tumor genome mutations at the same time. Here, we describe MIAmS, an application designed to tag microsatellite status from amplicon NGS of tumor samples. Interestingly, this tool does not require paired normal tissue for comparison. In addition, this scalable application provides a user-friendly report for the interpretation of the results by biologists and exhibits a strong accuracy and robustness for determination of the MSI status. AVAILABILITY: https://github.com/bialimed/miams. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online, evaluation data are available at http://www.ebi.ac.uk/ena/data/view/PRJEB31725.
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AIMS: Primary prostatic lymphomas (PPL) is exceedingly rare. The aim of this study was to investigate the largest series of PPL obtained from a nationwide expert pathologist network, and thus try to understand the pathophysiology of these tumours. METHODS AND RESULTS: Up to 66 000 lymphoma cases have been collected and submitted for central expert review by the French Lymphopath network. We confirm the low frequency of PPL (n = 77; 0.12%), all cases being of B-cell origin. Diffuse large B-cell lymphoma and small lymphocytic lymphoma were the most frequent subtypes, comprising 31% and 26% of cases respectively, followed by mucosa-associated lymphoid tissue (MALT)/lymphoplasmacytic lymphoma (19%), follicular lymphoma (12%), mantle cell lymphoma (6%), Burkitt lymphoma (4%), and unclassified lymphoma (1%). Clinical data obtained in 25 cases suggests that PPLs are rather indolent tumours. Our hypothesis for B-cell recruitment in the prostatic tissue was derived from the observation in chronic inflammation (prostatitis) of frequent heterotopic proliferation of high endothelial venules (HEVs). The latter are dedicated to lymphocyte entry into secondary lymphoid organs, here putatively driving circulating clonal B-lymphocytes from the blood into the inflamed prostate. This may account for the relatively high incidence of small lymphocytic lymphoma consistently reported in series of primary or secondary prostatic lymphoma. As in other organs or glands, chronic inflammation may promote antigen-dependent intraprostatic MALT lymphoma and diffuse large B-cell lymphoma development. CONCLUSIONS: PPLs are exclusively of B-cell origin, and chronic inflammation resulting from the proliferation of high endothelial venules could play some role in their development.
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Linfoma de Células B/patología , Neoplasias de la Próstata/patología , Prostatitis/patología , Adulto , Anciano , Anciano de 80 o más Años , Linfocitos B/patología , Humanos , Masculino , Persona de Mediana Edad , FenotipoRESUMEN
Amyloidoses are rare life-threatening diseases caused by protein misfolding of normally soluble proteins. The fatal outcome is predominantly due to renal failure and/or cardiac dysfunction. Because amyloid fibrils formed by all amyloidogenic proteins share structural similarity, amyloidoses may be studied in transgenic models expressing any amyloidogenic protein. Here we generated transgenic mice expressing an amyloidogenic variant of human apolipoprotein AII, a major protein of high density lipoprotein. According to amyloid nomenclature this variant was termed STOP78SERApoAII. STOP78SER-APOA2 expression at the physiological level spontaneously induced systemic amyloidosis in all mice with full-length mature STOP78SER-ApoAII identified as the amyloidogenic protein. Amyloid deposits stained with Congo red were extracellular, and consisted of fibrils of approximately 10 nm diameter. Renal glomerular amyloidosis was a major feature with onset of renal insufficiency occurring in mice older than six months of age. The liver, heart and spleen were also greatly affected. Expression of STOP78SER-APOA2 in the liver and intestine in mice of the K line but not in other amyloid-laden organs showed they present systemic amyloidosis. The amyloid burden was a function of STOP78SER-APOA2 expression and age of the mice with amyloid deposition starting in two-month-old high-expressing mice that died from six months onwards. Because STOP78SER-ApoAII conserved adequate lipid binding capacity as shown by high STOP78SER-ApoAII amounts in high density lipoprotein of young mice, its decrease in circulation with age suggests preferential deposition into preformed fibrils. Thus, our mouse model faithfully reproduces early-onset hereditary systemic amyloidosis and is ideally suited to devise and test novel therapies.
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Amiloidosis Familiar/genética , Apolipoproteína A-II/genética , Modelos Animales de Enfermedad , Amiloidosis Familiar/sangre , Amiloidosis Familiar/patología , Animales , Codón de Terminación/genética , Humanos , Glomérulos Renales/patología , Hígado/patología , Ratones , Ratones Transgénicos , Mutagénesis Sitio-Dirigida , Miocardio/patología , Bazo/patologíaRESUMEN
Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphomas are tumors that carry translocations involving the ALK gene at the 2p23 locus, leading to the expression of ALK tyrosine kinase fusion oncoproteins. Amongst hematologic malignancies, these lymphomas are particular in that they express very low levels of B-cell lymphoma 2 (BCL2), a recognized inhibitor of apoptosis and autophagy, two processes that share complex interconnections. We have previously shown that treatment of ALK-positive anaplastic large cell lymphoma cells with the ALK tyrosine kinase inhibitor crizotinib induces autophagy as a pro-survival response. Here, we observed that crizotinib-mediated inactivation of ALK caused an increase in BCL2 levels that restrained the cytotoxic effects of the drug. BCL2 downregulation in combination with crizotinib treatment potentiated loss of cell viability through both an increase in autophagic flux and cell death, including apoptosis. More importantly, our data revealed that the blockade of autophagic flux completely reversed impaired cell viability, which demonstrates that excessive autophagy is associated with cell death. We propose that the downregulation of BCL2 protein, which plays a central role in the autophagic and apoptotic machinery, combined with crizotinib treatment may represent a promising therapeutic alternative to current ALK-positive anaplastic large cell lymphoma treatments.
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Quinasa de Linfoma Anaplásico/metabolismo , Antineoplásicos/farmacología , Autofagia , Crizotinib/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Linfoma Anaplásico de Células Grandes/patología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Quinasa de Linfoma Anaplásico/genética , Animales , Muerte Celular , Proliferación Celular/efectos de los fármacos , Humanos , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Linfoma Anaplásico de Células Grandes/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones SCID , Pronóstico , Proteínas Proto-Oncogénicas c-bcl-2/genética , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Anaplastic large-cell lymphoma, a T-cell neoplasm, is primarily a pediatric disease. Seventy-five percent of pediatric anaplastic large-cell lymphoma cases harbor the chromosomal translocation t(2;5)(p23;q35) leading to the ectopic expression of NPM-ALK, a chimeric tyrosine kinase. NPM-ALK consists of an N-terminal nucleophosmin (NPM) domain fused to an anaplastic lymphoma kinase (ALK) cytoplasmic domain. Pediatric NPM-ALK+ anaplastic large-cell lymphoma is often a disseminated disease and young patients are prone to chemoresistance or relapse shortly after chemotherapeutic treatment. Furthermore, there is no gold standard protocol for the treatment of relapses. To the best of our knowledge, this is the first study on the potential role of the microRNA, miR-497, in NPM-ALK+ anaplastic large-cell lymphoma tumorigenesis. Our results show that miR-497 expression is repressed in NPM-ALK+ cell lines and patient samples through the hypermethylation of its promoter and the activity of NPM-ALK is responsible for this epigenetic repression. We demonstrate that overexpression of miR-497 in human NPM-ALK+ anaplastic large-cell lymphoma cells inhibits cellular growth and causes cell cycle arrest by targeting CDK6, E2F3 and CCNE1, the three regulators of the G1 phase of the cell cycle. Interestingly, we show that a scoring system based on CDK6, E2F3 and CCNE1 expression could help to identify relapsing pediatric patients. In addition, we demonstrate the sensitivity of NPM-ALK+ cells to CDK4/6 inhibition using for the first time a selective inhibitor, palbociclib. Together, our findings suggest that CDK6 could be a therapeutic target for the development of future treatments for NPM-ALK+ anaplastic large-cell lymphoma.
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Quinasa de Linfoma Anaplásico/metabolismo , Ciclo Celular/genética , Quinasa 6 Dependiente de la Ciclina/metabolismo , MicroARNs/genética , Quinasa de Linfoma Anaplásico/genética , Animales , Apoptosis/genética , Línea Celular Tumoral , Proliferación Celular , Quinasa 6 Dependiente de la Ciclina/genética , Metilación de ADN , Femenino , Regulación Neoplásica de la Expresión Génica , Xenoinjertos , Humanos , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/metabolismo , Linfoma Anaplásico de Células Grandes/patología , Ratones , Modelos Biológicos , Familia de Multigenes , Transducción de SeñalRESUMEN
PURPOSE OF REVIEW: Breast implant-associated anaplastic large cell lymphoma (BI-ALCL) is a rare form of lymphoma arising adjacent to a breast implant. We aim to review the pathogenesis and clinico-biological features of BI-ALCL. RECENT FINDINGS: BI-ALCL is a new provisional entity in the 2017 updated WHO classification. Among several hypotheses, BI-ALCL development seems to be determined by the interaction of immune response related to implant products and additional genetic events. SUMMARY: BI-ALCL is an uncommon T-cell lymphoma which is increasingly diagnosed since its first description in 1997 with 500 estimated cases worldwide. Two BI-ALCL subtypes correlating with clinical presentation have been described. Although most BI-ALCL patients with tumor cell proliferation restricted to the periprosthetic effusion and capsule have excellent outcomes, other patients presenting with a tumor mass, may have a more aggressive disease. The pathogenesis of BI-ALCL remains elusive. It is postulated that local chronic inflammation elicitated by bacterial infection or implant products may promote the activation and proliferation of T cells. Additional genetic events resulting in the activation JAK/STAT pathway are also incriminated. Further investigations are needed to better characterize the pathogenesis of this disease in order to determine the potential risk to develop BI-ALCL after surgical implants.
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Implantes de Mama/efectos adversos , Linfoma Anaplásico de Células Grandes/etiología , Adulto , Anciano , Anciano de 80 o más Años , Implantación de Mama/efectos adversos , Implantación de Mama/instrumentación , Neoplasias de la Mama/cirugía , Femenino , Humanos , Linfoma Anaplásico de Células Grandes/inmunología , Linfoma Anaplásico de Células Grandes/patología , Mastectomía , Persona de Mediana EdadRESUMEN
Acute basophilic leukaemia (ABL) is a rare subtype of acute myeloblastic leukaemia. We previously described a recurrent t(X;6)(p11;q23) translocation generating an MYB-GATA1 fusion gene in male infants with ABL. To better understand its role, the chimeric MYB-GATA1 transcription factor was expressed in CD34-positive haematopoietic progenitors, which were transplanted into immunodeficient mice. Cells expressing MYB-GATA1 showed increased expression of markers of immaturity (CD34), of granulocytic lineage (CD33 and CD117), and of basophilic differentiation (CD203c and FcϵRI). UT-7 cells also showed basophilic differentiation after MYB-GATA1 transfection. A transcriptomic study identified nine genes deregulated by both MYB-GATA1 and basophilic differentiation. Induction of three of these genes (CCL23, IL1RL1, and NTRK1) was confirmed in MYB-GATA1-expressing CD34-positive cells by reverse transcription quantitative polymerase chain reaction. Interleukin (IL)-33 and nerve growth factor (NGF), the ligands of IL-1 receptor-like 1 (IL1RL1) and neurotrophic receptor tyrosine kinase 1 (NTRK1), respectively, enhanced the basophilic differentiation of MYB-GATA1-expressing UT-7 cells, thus demonstrating the importance of this pathway in the basophilic differentiation of leukaemic cells and CD34-positive primary cells. Finally, gene reporter assays confirmed that MYB and MYB-GATA1 directly activated NTRK1 and IL1RL1 transcription, leading to basophilic skewing of the blasts. MYB-GATA1 is more efficient than MYB, because of better stability. Our results highlight the role of IL-33 and NGF receptors in the basophilic differentiation of normal and leukaemic cells. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Interleucina-33/fisiología , Leucemia Basofílica Aguda/etiología , Receptores de Factor de Crecimiento Nervioso/fisiología , Animales , Transformación Celular Neoplásica/genética , Femenino , Factor de Transcripción GATA1/genética , Fusión Génica/fisiología , Células Madre Hematopoyéticas/fisiología , Masculino , Ratones SCID , Trasplante de Neoplasias , Proteínas Oncogénicas v-myb/genética , Receptor trkA/metabolismo , Factores de Transcripción/metabolismo , Transfección , Trasplante HeterólogoRESUMEN
Long non-coding RNAs are defined as transcripts larger than 200 nucleotides but without protein-coding potential. There is growing evidence of the important role of long non-coding RNAs in cancer initiation, development and progression. In this study, we sought to evaluate the long non-coding RNA expression profile of patients with cytogenetically normal acute myeloid leukemia (AML). RNA-sequencing of 40 cytogenetically normal AML patients allowed us to quantify 11,036 long non-coding RNAs. Among these, more than 8000 were previously undescribed long non-coding RNAs. Using unsupervised analysis, we observed a specific long non-coding RNA expression profile dependent on the mutational status of the NPM1 gene. Statistical analysis allowed us to identify a minimal set of 12 long non-coding RNAs capable of discriminating NPM1-mutated from NPM1-wild-type patients. These results were validated by qRT-PCR on an independent cohort composed of 134 cytogenetically normal AML patients. Furthermore, we have identified one putative biomarker, the long non-coding RNA XLOC_109948 whose expression pattern predicts clinical outcome. Interestingly, low XLOC_109948 expression indicates a good prognosis especially for NPM1-mutated patients. Transient transfection of GapmeR against XLOC_109948 in NPM1-mutated OCI-AML3 cell line treated with Ara-C or ATRA enhances apoptosis suggesting XLOC_109948 plays a role in drug sensitivity. This study improves our knowledge of the long non-coding RNA transcriptome in cytogenetically normal AML patients. We observed a distinct long non-coding RNA expression profile in patients with the NPM1 mutation. The newly identified XLOC_109948 long non-coding RNA emerged as a strong prognostic factor able to better stratify NPM1-mutated patients.
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Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Mutación , Proteínas Nucleares/genética , ARN Largo no Codificante/genética , Transcriptoma , Apoptosis/genética , Biomarcadores , Línea Celular Tumoral , Análisis por Conglomerados , Perfilación de la Expresión Génica , Regulación Leucémica de la Expresión Génica , Humanos , Cariotipo , Leucemia Mieloide Aguda/mortalidad , Nucleofosmina , Pronóstico , Análisis de Secuencia de ARNAsunto(s)
Amiloidosis , Proteómica , Humanos , Amiloide , Espectrometría de Masas , Estudios de CohortesRESUMEN
AIMS: Inflammatory myofibroblastic tumours (IMTs) usually have a soft tissue and visceral localization, but have been rarely reported in skin. The aim of this study was to characterize the histological and immunohistochemical features of a series of cutaneous IMTs. METHODS AND RESULTS: We retrieved from our archives over 10 years four cutaneous IMTs; one was diagnosed in a child, and three in young adults. Tumours were centred on the dermis, and also involved the subcutis in two cases. Two of them corresponded to the 'myxoid-vascular' pattern of IMT, whereas the others were characterized by compact fascicles of spindle-shaped cells. They stained positively for smooth muscle actin. All samples stained positively for anaplastic lymphoma kinase (ALK). ALK expression was limited to the cytoplasm of myofibroblasts and, in the three investigated cases, correlated with ALK rearrangement as shown by fluorescence in-situ hybridization analysis. CONCLUSIONS: This is the first report of ALK-positive IMTs with a cutaneous localization. Because of their morphological heterogeneity and low incidence in skin, the diagnosis of cutaneous IMTs is often challenging. A cutaneous spindled cell tumour associated with an inflammatory infiltrate should prompt pathologists to perform ALK staining, which, if positive, might be decisive for diagnosis.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Neoplasias Cutáneas/diagnóstico , Actinas/análisis , Adulto , Quinasa de Linfoma Anaplásico , Niño , Femenino , Humanos , Hibridación Fluorescente in Situ , Masculino , Miofibroblastos/patología , Proteínas Tirosina Quinasas/biosíntesis , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/cirugíaRESUMEN
Plasmablastic lymphoma is a rare and aggressive diffuse large B-cell lymphoma commonly associated with Epstein-Barr virus co-infection that most often occurs in the context of human immunodeficiency virus infection. Therefore, its immune escape strategy may involve the upregulation of immune-checkpoint proteins allowing the tumor immune evasion. However, the expression of these molecules was poorly studied in this lymphoma. We have investigated 82 plasmablastic lymphoma cases of whom half were Epstein-Barr virus positive. Although they harbored similar pathological features, Epstein-Barr virus positive plasmablastic lymphomas showed a significant increase in MYC gene rearrangement and had a better 2-year event-free survival than Epstein-Barr virus negative cases (P=0.049). Immunostains for programmed cell death-1, programmed cell death-ligand 1, indole 2,3-dioxygenase and dendritic cell specific C-type lectin showed a high or moderate expression by the microenvironment cells in 60%-72% of cases, whereas CD163 was expressed in almost all cases. Tumor cells also expressed programmed cell death-1 and its ligand in 22.5% and 5% of cases, respectively. Both Epstein-Barr virus positive and negative plasmablastic lymphomas exhibited a high immune-checkpoint score showing that it involves several pathways of immune escape. However, Epstein-Barr virus positive lymphomas exhibited a higher expression of programmed cell death-1 and its ligand in both malignant cells and microenvironment as compared to Epstein-Barr virus negative cases. In conclusion, plasmablastic lymphoma expresses immune-checkpoint proteins through both malignant cells and the tumor microenvironment. The expression of programmed cell death-1 and its ligand constitutes a strong rationale for testing monoclonal antibodies in this often chemoresistant disease.