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1.
Cell ; 176(6): 1265-1281.e24, 2019 03 07.
Artículo en Inglés | MEDLINE | ID: mdl-30827681

RESUMEN

Acute myeloid leukemia (AML) is a heterogeneous disease that resides within a complex microenvironment, complicating efforts to understand how different cell types contribute to disease progression. We combined single-cell RNA sequencing and genotyping to profile 38,410 cells from 40 bone marrow aspirates, including 16 AML patients and five healthy donors. We then applied a machine learning classifier to distinguish a spectrum of malignant cell types whose abundances varied between patients and between subclones in the same tumor. Cell type compositions correlated with prototypic genetic lesions, including an association of FLT3-ITD with abundant progenitor-like cells. Primitive AML cells exhibited dysregulated transcriptional programs with co-expression of stemness and myeloid priming genes and had prognostic significance. Differentiated monocyte-like AML cells expressed diverse immunomodulatory genes and suppressed T cell activity in vitro. In conclusion, we provide single-cell technologies and an atlas of AML cell states, regulators, and markers with implications for precision medicine and immune therapies. VIDEO ABSTRACT.


Asunto(s)
Leucemia Mieloide Aguda/genética , Transcriptoma/genética , Adulto , Secuencia de Bases/genética , Médula Ósea , Células de la Médula Ósea/citología , Línea Celular Tumoral , Progresión de la Enfermedad , Femenino , Genotipo , Humanos , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/fisiopatología , Aprendizaje Automático , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , ARN , Transducción de Señal , Análisis de la Célula Individual/métodos , Microambiente Tumoral , Secuenciación del Exoma/métodos
2.
Cell ; 173(1): 90-103.e19, 2018 03 22.
Artículo en Inglés | MEDLINE | ID: mdl-29551269

RESUMEN

Blood cell formation is classically thought to occur through a hierarchical differentiation process, although recent studies have shown that lineage commitment may occur earlier in hematopoietic stem and progenitor cells (HSPCs). The relevance to human blood diseases and the underlying regulation of these refined models remain poorly understood. By studying a genetic blood disorder, Diamond-Blackfan anemia (DBA), where the majority of mutations affect ribosomal proteins and the erythroid lineage is selectively perturbed, we are able to gain mechanistic insight into how lineage commitment is programmed normally and disrupted in disease. We show that in DBA, the pool of available ribosomes is limited, while ribosome composition remains constant. Surprisingly, this global reduction in ribosome levels more profoundly alters translation of a select subset of transcripts. We show how the reduced translation of select transcripts in HSPCs can impair erythroid lineage commitment, illuminating a regulatory role for ribosome levels in cellular differentiation.


Asunto(s)
Anemia de Diamond-Blackfan/patología , Ribosomas/metabolismo , Regiones no Traducidas 5' , Anemia de Diamond-Blackfan/genética , Proteínas Reguladoras de la Apoptosis/antagonistas & inhibidores , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Células de la Médula Ósea/metabolismo , Células Cultivadas , Femenino , Factor de Transcripción GATA1/genética , Factor de Transcripción GATA1/metabolismo , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Humanos , Masculino , Mutación Missense , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Proteínas Ribosómicas/antagonistas & inhibidores , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismo , Ribosomas/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
3.
Mod Pathol ; 37(1): 100352, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37839675

RESUMEN

In this study, we performed a comprehensive molecular analysis of paired skin and peripheral blood/bone marrow (BM) samples from 17 patients with cutaneous myeloid or cutaneous histiocytic-dendritic neoplasms. The cutaneous manifestations included 10 patients with cutaneous acute myeloid leukemia (c-AML), 2 patients with full or partial Langerhans cell differentiation, 2 patients with blastic plasmacytoid dendritic cell neoplasms (BPDCN), 1 patient with both Langerhans cell differentiation and BPDCN, and 2 patients with full or partial indeterminate dendritic cell differentiation. Seven of the 10 c-AML patients (70%) exhibited concurrent or subsequent marrow involvement by acute myeloid leukemia, with all 7 cases (100%) demonstrating shared clonal mutations in both the skin and BM. However, clonal relatedness was documented in one additional case that never had any BM involvement. Nevertheless, NPM1 mutations were identified in 7 of the 10 (70%) of these c-AML cases while one had KMT2A rearrangement and one showed inv(16). All 3 patients (100%) with Langerhans cell neoplasms, 2 patients with BPDCN (100%), and one of the 2 patients (50%) with other cutaneous dendritic cell neoplasms also demonstrated shared mutations between the skin and concurrent or subsequent myeloid neoplasms. Both BM and c-AML shared identical founding drivers, with a predominance of NPM1, DNMT3A, and translocations associated with monocytic differentiation, with common cutaneous-only mutations involving genes in the signal transduction and epigenetic pathways. Cutaneous histiocytic-dendritic neoplasms shared founding drivers in ASXL1, TET2, and/or SRSF2. However, in the Langerhans cell histiocytosis or histiocytic sarcoma cases, there exist recurrent secondary RAS pathway hits, whereas cutaneous BPDCN cases exhibit copy number or structural variants. These results enrich and broaden our understanding of clonally related cutaneous manifestations of myeloid neoplasms and further illuminate the highly diverse spectrum of morphologic and immunophenotypic features they exhibit.


Asunto(s)
Neoplasias Hematológicas , Leucemia Mieloide Aguda , Trastornos Mieloproliferativos , Neoplasias Cutáneas , Humanos , Médula Ósea/patología , Células Dendríticas/metabolismo , Mutación , Leucemia Mieloide Aguda/patología , Neoplasias Hematológicas/patología , Neoplasias Cutáneas/patología , Trastornos Mieloproliferativos/patología , Proteínas Nucleares/genética
4.
Blood ; 137(14): 1905-1919, 2021 04 08.
Artículo en Inglés | MEDLINE | ID: mdl-33751108

RESUMEN

Chromosome 13q deletion [del(13q)], harboring the miR-15a/16-1 cluster, is one of the most common genetic alterations in mature B-cell malignancies, which originate from germinal center (GC) and post-GC B cells. Moreover, miR-15a/16 expression is frequently reduced in lymphoma and multiple myeloma (MM) cells without del(13q), suggesting important tumor-suppressor activity. However, the role of miR-15a/16-1 in B-cell activation and initiation of mature B-cell neoplasms remains to be determined. We show that conditional deletion of the miR-15a/16-1 cluster in murine GC B cells induces moderate but widespread molecular and functional changes including an increased number of GC B cells, percentage of dark zone B cells, and maturation into plasma cells. With time, this leads to development of mature B-cell neoplasms resembling human extramedullary plasmacytoma (EP) as well as follicular and diffuse large B-cell lymphomas. The indolent nature and lack of bone marrow involvement of EP in our murine model resembles human primary EP rather than MM that has progressed to extramedullary disease. We corroborate human primary EP having low levels of miR-15a/16 expression, with del(13q) being the most common genetic loss. Additionally, we show that, although the mutational profile of human EP is similar to MM, there are some exceptions such as the low frequency of hyperdiploidy in EP, which could account for different disease presentation. Taken together, our studies highlight the significant role of the miR-15a/16-1 cluster in the regulation of the GC reaction and its fundamental context-dependent tumor-suppression function in plasma cell and B-cell malignancies.


Asunto(s)
Linfoma de Células B Grandes Difuso/genética , MicroARNs/genética , Neoplasias de Células Plasmáticas/genética , Animales , Linfocitos B/metabolismo , Linfocitos B/patología , Deleción Cromosómica , Trastornos de los Cromosomas/genética , Trastornos de los Cromosomas/patología , Cromosomas Humanos Par 13/genética , Eliminación de Gen , Regulación Neoplásica de la Expresión Génica , Humanos , Linfoma de Células B Grandes Difuso/patología , Ratones Endogámicos C57BL , Familia de Multigenes , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Neoplasias de Células Plasmáticas/patología , Células Plasmáticas/metabolismo , Células Plasmáticas/patología , Plasmacitoma/genética , Plasmacitoma/patología
5.
Am J Dermatopathol ; 45(8): 577-581, 2023 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-37462207

RESUMEN

ABSTRACT: Classic Hodgkin lymphoma (CHL) is a B-cell-derived lymphoma that classically displays a bimodal age distribution. CHL typically involves the mediastinum, lymph nodes, and other visceral organs. CHL is characterized histologically by the presence of a relatively paucicellular neoplastic cell population composed of large atypical cells (including Hodgkin and Reed-Sternberg forms) in a reactive mixed inflammatory background, often with prominent necrosis. CHL rarely occurs in the skin, and the associated mixed inflammatory infiltrate or necrotic appearance can create diagnostic uncertainty. Herein, we report the case of a 31-year-old man presenting with a painful dendritic rash of the anterior chest wall with axillary lymphadenopathy. After multiple nondiagnostic biopsies that revealed largely necrotic material, a chest wall skin biopsy was obtained. The skin biopsy was diagnostic of CHL, based on the presence of large atypical dermal cells, including Hodgkin and Reed-Sternberg forms, which expressed CD15, CD30 and Fascin, in a typical mixed inflammatory and necrotic background. Through the lens of this case, we discuss the characteristics and mechanisms of skin involvement of CHL, and the histopathologic and immunohistochemical pitfalls when considering the rare diagnosis of CHL in the skin.


Asunto(s)
Enfermedad de Hodgkin , Linfoma de Células B , Neoplasias Cutáneas , Masculino , Humanos , Adulto , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/patología , Linfoma de Células B/patología , Piel/patología , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/patología , Biopsia
6.
Histopathology ; 81(5): 600-624, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-35925828

RESUMEN

Thromboembolic phenomena are an important complication of infection by severe acute respiratory coronavirus 2 (SARS-CoV-2). Increasing focus on the management of the thrombotic complications of Coronavirus Disease 2019 (COVID-19) has led to further investigation into the role of platelets, and their precursor cell, the megakaryocyte, during the disease course. Previously published postmortem evaluations of patients who succumbed to COVID-19 have reported the presence of megakaryocytes in the cardiac microvasculature. Our series evaluated a cohort of autopsies performed on SARS-CoV-2-positive patients in 2020 (n = 36) and prepandemic autopsies performed in early 2020 (n = 12) and selected to represent comorbidities common in cases of severe COVID-19, in addition to infectious and noninfectious pulmonary disease and thromboembolic phenomena. Cases were assessed for the presence of cardiac megakaryocytes and correlated with the presence of pulmonary emboli and laboratory platelet parameters and inflammatory markers. Cardiac megakaryocytes were detected in 64% (23/36) of COVID-19 autopsies, and 40% (5/12) prepandemic autopsies, with averages of 1.77 and 0.84 megakaryocytes per cm2 , respectively. Within the COVID-19 cohort, autopsies with detected megakaryocytes had significantly higher platelet counts compared with cases throughout; other platelet parameters were not statistically significant between groups. Although studies have supported a role of platelets and megakaryocytes in the response to viral infections, including SARS-CoV-2, our findings suggest cardiac megakaryocytes may be representative of a nonspecific inflammatory response and are frequent in, but not exclusive to, COVID-19 autopsies.


Asunto(s)
COVID-19 , SARS-CoV-2 , Autopsia , Humanos , Pulmón , Megacariocitos
7.
Mod Pathol ; 33(6): 1135-1145, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-31896808

RESUMEN

Greater than 90% of cases of systemic mastocytosis (SM) harbor pathogenic KIT mutations, particularly KITD816V. Prognostically-significant pathogenic KIT mutations also occur in 30-40% of core binding factor-associated acute myeloid leukemia (CBF-AML), but are uncommonly associated with concurrent SM. By comparison, the occurrence of SM in other myeloid neoplasms bearing pathogenic KIT mutations, particularly those with a chronic course, is poorly understood. Review of clinical next-generation sequencing (NGS) performed at our institutions in patients with known or suspected hematologic malignancies over an 8-year period revealed 64 patients with both a pathogenic KIT mutation detected at one or more timepoints and available bone marrow biopsy materials. Patients with KITD816V-mutated myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), or overlap MDS/MPN (n = 22) accounted for approximately one-third of our cohort (34%). Comprehensive morphologic and immunophenotypic characterization revealed that nearly all cases (n = 20, 91%) exhibited concurrent SM. In contrast, of the 18 patients (28%) with AML and KITD816V, only eight (44%) showed evidence of SM at any point in their disease course (p = 0.0021); of these eight, the AML component was characterized as AML with myelodysplasia-related changes (AML-MRC) in all but one instance (n = 7, 87%). Twelve patients (19%) had pathogenic KIT mutations other than p.D816V, all in the setting of AML (CFB-AML, n = 7; AML, not otherwise specified, n = 2; AML-MRC, n = 1; acute promyelocytic leukemia, n = 1); only two of these patients (17%), both with CBF-AML, exhibited concurrent SM. The remaining 12 patients (19%) had SM without evidence of an associated hematological neoplasm (AHN). For nearly one-third of the 30 SM-AHN patients in our cohort (n = 9, 30%), the SM component of their disease was not initially clinicopathologically recognized. We propose that identification of the KITD816V mutation in patients diagnosed with MDS, MPN, MDS/MPN, or AML-MRC should trigger reflex testing for SM.


Asunto(s)
Leucemia Mieloide Aguda/genética , Mastocitosis/genética , Síndromes Mielodisplásicos/genética , Trastornos Mieloproliferativos/genética , Proteínas Proto-Oncogénicas c-kit/genética , Análisis Mutacional de ADN , Humanos , Leucemia Mieloide Aguda/patología , Mastocitosis/patología , Mutación , Síndromes Mielodisplásicos/patología , Trastornos Mieloproliferativos/patología
8.
Mod Pathol ; 33(7): 1380-1388, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32051557

RESUMEN

Ancillary testing during the initial workup of acute myeloid leukemia (AML) is largely performed using aspirated materials. We utilized multiplex immunofluorescence (MIF) imaging with digital image analysis to perform an in situ analysis of the microenvironment in NPM1-mutated AML using diagnostic bone marrow biopsy tissues (N = 17) and correlated these findings with diagnostic next-generation sequencing (NGS, N = 17), flow cytometry (FC, N = 14), and first remission (CR1) NPM1-specific molecular MRD (n = 16) data. The total CD3-positive T-cell percentages correlated positively between FC and MIF (r = 0.53, p = 0.05), but were significantly lower by MIF (1.62% vs. 3.4%, p = 0.009). The percentage of mutant NPM1-positive (NPM1c+) cells ranged from 9.7 to 90.8% (median 45.4%) and did not correlate with the NPM1 mutant allele fraction by NGS (p > 0.05). The percentage of CD34+/NPM1c+ cells ranged from 0 to 1.8% (median 0.07%). The percentage of NPM1c+ cells correlated inversely (34% vs. 62%, p = 0.03), while the percentages of CD3-/NPM1c- cells (64% vs. 35%, p = 0.03), and specifically CD3-/CD4-/NPM1c- cells (26% vs. 13%, p = 0.04), correlated positively with subsequent MRD. Discordances between MIF and FC/NGS data suggest that aspirate materials are likely an imperfect reflection of the core biopsy tissue. Furthermore, increased numbers of NPM1 wild-type cells within the microenvironment at diagnosis correlate with the subsequent presence of MRD.


Asunto(s)
Médula Ósea/patología , Interpretación de Imagen Asistida por Computador/métodos , Leucemia Mieloide Aguda/patología , Microambiente Tumoral , Adulto , Anciano , Femenino , Técnica del Anticuerpo Fluorescente/métodos , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Proteínas Nucleares/genética , Nucleofosmina , Pronóstico
9.
Am J Hematol ; 94(8): 921-928, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31148220

RESUMEN

Acute myeloid leukemia (AML) with mutated NPM1 is a newly recognized separate entity in the revised 2016 WHO classification, and is associated with a favorable prognosis. While previous studies have evaluated NPM1 in a binary fashion, we recently demonstrated a significant independent negative prognostic effect of high NPM1 mutant allele burden (VAF) at diagnosis in a cohort of de novo AML patients. Although the importance of minimal residual disease (MRD) monitoring in NPM1-mutated AML has been well characterized, the potential relationship between diagnostic allele burden and MRD is unknown. We retrospectively evaluated for MRD at first remission (CR1). We used either next-generation sequencing (NGS) [n = 71], and/or immunohistochemistry (IHC) for mutant NPM1 (NPM1c) [n = 60], in a subset of patients from our recently examined cohort. We identified a statistically significant positive correlation between the VAF at diagnosis, and at CR1 (Spearman r = 0.4, P = .006), and enrichment for MRD in high diagnostic VAF patients (P = .05), as previously defined. IHC-positivity also correlated significantly with a higher median diagnostic NPM1 VAF (0.42 vs 0.39, P = .02), and with the VAF at CR1 (Spearman r = 0.7, P = .003). In multivariable analyses, both high diagnostic VAF (P = .003) and MRD (P = .02) were independent predictors of shorter event-free survival (EFS). Our findings suggest a relationship between the NPM1 mutant allele burden at diagnosis, and the presence of MRD at first remission. Our findings support IHC as a potentially useful adjunctive tool for disease monitoring.


Asunto(s)
Leucemia Mieloide Aguda/genética , Neoplasia Residual/genética , Proteínas Nucleares/genética , Inducción de Remisión , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Femenino , Frecuencia de los Genes , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Mutación , Neoplasia Residual/mortalidad , Nucleofosmina , Pronóstico , Recurrencia , Análisis de Supervivencia
10.
Blood ; 127(7): 869-81, 2016 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-26702065

RESUMEN

Primary central nervous system lymphomas (PCNSLs) and primary testicular lymphomas (PTLs) are extranodal large B-cell lymphomas (LBCLs) with inferior responses to current empiric treatment regimens. To identify targetable genetic features of PCNSL and PTL, we characterized their recurrent somatic mutations, chromosomal rearrangements, copy number alterations (CNAs), and associated driver genes, and compared these comprehensive genetic signatures to those of diffuse LBCL and primary mediastinal large B-cell lymphoma (PMBL). These studies identify unique combinations of genetic alterations in discrete LBCL subtypes and subtype-selective bases for targeted therapy. PCNSLs and PTLs frequently exhibit genomic instability, and near-uniform, often biallelic, CDKN2A loss with rare TP53 mutations. PCNSLs and PTLs also use multiple genetic mechanisms to target key genes and pathways and exhibit near-uniform oncogenic Toll-like receptor signaling as a result of MYD88 mutation and/or NFKBIZ amplification, frequent concurrent B-cell receptor pathway activation, and deregulation of BCL6. Of great interest, PCNSLs and PTLs also have frequent 9p24.1/PD-L1/PD-L2 CNAs and additional translocations of these loci, structural bases of immune evasion that are shared with PMBL.


Asunto(s)
Neoplasias del Sistema Nervioso Central/genética , Sitios Genéticos , Linfoma de Células B Grandes Difuso/genética , Proteínas de Neoplasias/genética , Neoplasias Testiculares/genética , Translocación Genética , Neoplasias del Sistema Nervioso Central/metabolismo , Neoplasias del Sistema Nervioso Central/patología , Femenino , Humanos , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Masculino , Neoplasias del Mediastino/genética , Neoplasias del Mediastino/metabolismo , Neoplasias del Mediastino/patología , Proteínas de Neoplasias/metabolismo , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patología
11.
Blood ; 127(18): 2203-13, 2016 05 05.
Artículo en Inglés | MEDLINE | ID: mdl-26773040

RESUMEN

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease defined by transcriptional classifications, specific signaling and survival pathways, and multiple low-frequency genetic alterations. Preclinical model systems that capture the genetic and functional heterogeneity of DLBCL are urgently needed. Here, we generated and characterized a panel of large B-cell lymphoma (LBCL) patient-derived xenograft (PDX) models, including 8 that reflect the immunophenotypic, transcriptional, genetic, and functional heterogeneity of primary DLBCL and 1 that is a plasmablastic lymphoma. All LBCL PDX models were subjected to whole-transcriptome sequencing to classify cell of origin and consensus clustering classification (CCC) subtypes. Mutations and chromosomal rearrangements were evaluated by whole-exome sequencing with an extended bait set. Six of the 8 DLBCL models were activated B-cell (ABC)-type tumors that exhibited ABC-associated mutations such as MYD88, CD79B, CARD11, and PIM1. The remaining 2 DLBCL models were germinal B-cell type, with characteristic alterations of GNA13, CREBBP, and EZH2, and chromosomal translocations involving IgH and either BCL2 or MYC Only 25% of the DLBCL PDX models harbored inactivating TP53 mutations, whereas 75% exhibited copy number alterations of TP53 or its upstream modifier, CDKN2A, consistent with the reported incidence and type of p53 pathway alterations in primary DLBCL. By CCC criteria, 6 of 8 DLBCL PDX models were B-cell receptor (BCR)-type tumors that exhibited selective surface immunoglobulin expression and sensitivity to entospletinib, a recently developed spleen tyrosine kinase inhibitor. In summary, we have established and characterized faithful PDX models of DLBCL and demonstrated their usefulness in functional analyses of proximal BCR pathway inhibition.


Asunto(s)
Linfoma de Células B Grandes Difuso/genética , Animales , Linaje de la Célula , Aberraciones Cromosómicas , Regulación Neoplásica de la Expresión Génica , Genes Relacionados con las Neoplasias , Heterogeneidad Genética , Xenoinjertos , Humanos , Inmunofenotipificación , Linfoma de Células B Grandes Difuso/patología , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Mutación , Análisis de Secuencia de ADN , Ensayo de Capsula Subrrenal , Transcriptoma
12.
Histopathology ; 71(1): 112-124, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28261866

RESUMEN

AIMS: Hairy cell leukaemia (HCL) is a rare B cell neoplasm that mainly affects bone marrow (BM), peripheral blood (PB) and spleen. Involvement of lymph nodes and extranodal structures is considered infrequent. Herein we describe our institutional experience of nodal (n = 10) and extranodal (n = 3) HCL during a 30-year period. METHODS AND RESULTS: Ten patients had prior evidence of HCL within the BM or PB at a median 35.8 months before nodal/extranodal diagnosis (range: <1-175 months), and HCL was diagnosed concurrently within the bone marrow of one additional patient. Nodal involvement showed distinct architectural patterns, including diffuse (62% of cases), sinusoidal (25%) and nodular (13%). Extranodal involvement was characterized as diffuse infiltration through underlying structures in all cases. Morphological features ranged from classic 'fried-egg' cytology to a plasmacytoid appearance. Nodal/extranodal disease showed an overlapping immunophenotypical profile with other small B cell lymphomas, including expression of cyclin D1 (70%), CD43 (55%), CD10 (38%) and CD5 (8%). Rates of both CD43 and CD10 reactivity were higher than described previously in leukaemic HCL, suggesting that expression may be enriched in cases with extramedullary extension. CONCLUSIONS: Although uncommon, HCL should be considered in the differential diagnosis of small B cell neoplasms involving nodal/extranodal sites, given the therapeutic implications. In particular, recent discoveries including detection of the BRAFV600E mutation in nearly all cases of HCL and the availability of an antibody to CD103 for use in paraffin-embedded tissues will facilitate the distinction of HCL from other small B cell lymphomas in the nodal/extranodal setting.


Asunto(s)
Leucemia de Células Pilosas/patología , Ganglios Linfáticos/patología , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Femenino , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad
14.
N Engl J Med ; 367(9): 826-33, 2012 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-22931316

RESUMEN

BACKGROUND: Waldenström's macroglobulinemia is an incurable, IgM-secreting lymphoplasmacytic lymphoma (LPL). The underlying mutation in this disorder has not been delineated. METHODS: We performed whole-genome sequencing of bone marrow LPL cells in 30 patients with Waldenström's macroglobulinemia, with paired normal-tissue and tumor-tissue sequencing in 10 patients. Sanger sequencing was used to validate the findings in samples from an expanded cohort of patients with LPL, those with other B-cell disorders that have some of the same features as LPL, and healthy donors. RESULTS: Among the patients with Waldenström's macroglobulinemia, a somatic variant (T→C) in LPL cells was identified at position 38182641 at 3p22.2 in the samples from all 10 patients with paired tissue samples and in 17 of 20 samples from patients with unpaired samples. This variant predicted an amino acid change (L265P) in MYD88, a mutation that triggers IRAK-mediated NF-κB signaling. Sanger sequencing identified MYD88 L265P in tumor samples from 49 of 54 patients with Waldenström's macroglobulinemia and in 3 of 3 patients with non-IgM-secreting LPL (91% of all patients with LPL). MYD88 L265P was absent in paired normal tissue samples from patients with Waldenström's macroglobulinemia or non-IgM LPL and in B cells from healthy donors and was absent or rarely expressed in samples from patients with multiple myeloma, marginal-zone lymphoma, or IgM monoclonal gammopathy of unknown significance. Inhibition of MYD88 signaling reduced IκBα and NF-κB p65 phosphorylation, as well as NF-κB nuclear staining, in Waldenström's macroglobulinemia cells expressing MYD88 L265P. Somatic variants in ARID1A in 5 of 30 patients (17%), leading to a premature stop or frameshift, were also identified and were associated with an increased disease burden. In addition, 2 of 3 patients with Waldenström's macroglobulinemia who had wild-type MYD88 had somatic variants in MLL2. CONCLUSIONS: MYD88 L265P is a commonly recurring mutation in patients with Waldenström's macroglobulinemia that can be useful in differentiating Waldenström's macroglobulinemia and non-IgM LPL from B-cell disorders that have some of the same features. (Funded by the Peter and Helen Bing Foundation and others.).


Asunto(s)
Mutación , Factor 88 de Diferenciación Mieloide/genética , Macroglobulinemia de Waldenström/genética , Diagnóstico Diferencial , Progresión de la Enfermedad , Expresión Génica , Genoma Humano , Humanos , Inmunoglobulina M/análisis , Paraproteinemias/diagnóstico , Paraproteinemias/inmunología , Análisis de Secuencia de ADN , Macroglobulinemia de Waldenström/diagnóstico , Macroglobulinemia de Waldenström/inmunología
15.
Cancer Cell ; 11(4): 349-60, 2007 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-17418411

RESUMEN

Multiple myeloma (MM) evolves from a highly prevalent premalignant condition termed MGUS. The factors underlying the malignant transformation of MGUS are unknown. We report a MGUS/MM phenotype in transgenic mice with Emu-directed expression of the XBP-1 spliced isoform (XBP-1s), a factor governing unfolded protein/ER stress response and plasma-cell development. Emu-XBP-1s elicited elevated serum Ig and skin alterations. With age, Emu-xbp-1s transgenics develop features diagnostic of human MM, including bone lytic lesions and subendothelial Ig deposition. Furthermore, transcriptional profiles of Emu-xbp-1s lymphoid and MM cells show aberrant expression of known human MM dysregulated genes. The similarities of this model with the human disease, coupled with documented frequent XBP-1s overexpression in human MM, serve to implicate XBP-1s dysregulation in MM pathogenesis.


Asunto(s)
Diferenciación Celular , Proteínas de Unión al ADN/metabolismo , Retículo Endoplásmico/patología , Mieloma Múltiple/patología , Proteínas Nucleares/metabolismo , Células Plasmáticas/citología , Envejecimiento/patología , Animales , Linfocitos B/metabolismo , Linfocitos B/patología , Enfermedades Óseas/patología , Células Cultivadas , Proteínas de Unión al ADN/genética , Dromaiidae/genética , Ensayo de Cambio de Movilidad Electroforética , Retículo Endoplásmico/metabolismo , Femenino , Humanos , Hipergammaglobulinemia/patología , Enfermedades Renales/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mieloma Múltiple/metabolismo , Proteínas Nucleares/genética , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Empalme del ARN , Factores de Transcripción del Factor Regulador X , Enfermedades de la Piel/patología , Factores de Transcripción , Transcripción Genética , Proteína 1 de Unión a la X-Box
16.
Blood ; 120(12): 2395-404, 2012 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-22855608

RESUMEN

Pediatric follicular lymphoma (PFL) is a variant of follicular lymphoma (FL) presenting as localized lymphadenopathy in children. Unlike conventional adult FL, PFL typically does not recur or progress. Clear diagnostic criteria for PFL are lacking, and it is uncertain whether this indolent lymphoma is defined by age or may occur in adults. We analyzed 27 FL in patients < 40 years of age and found that all 21 cases that lacked a BCL2 gene abnormality (BCL2-N; P < .0001) and had > 30% Ki67 fraction (high proliferation index, HPI; P = .0007) were stage I and did not progress or recur; in comparison, all 6 cases with BCL2 rearrangement and/or PI < 30% were stage III/IV, and 5 of 6 recurred or progressed. In a separate cohort of 58 adult FL (≥ 18 years of age), all 13 BCL2-N/HPI cases were stage I, and none progressed or relapsed, whereas 11 of 15 stage I cases with BCL2 gene abnormality and/or LPI relapsed or progressed (P = .0001). The adult and pediatric BCL2-N/HPI FL cases had similar morphologic features. Our results confirm the highly indolent behavior of PFL and suggest that these are characterized by HPI and absence of BCL2 gene abnormality. PFL-like cases also occur in adults and are associated with indolent behavior in this patient population.


Asunto(s)
Proliferación Celular , Reordenamiento Génico/genética , Ganglios Linfáticos/patología , Linfoma Folicular/genética , Linfoma Folicular/patología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Inmunofenotipificación , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Antígeno Ki-67/metabolismo , Linfoma Folicular/mortalidad , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Pronóstico , Tasa de Supervivencia , Adulto Joven
18.
J Immunol ; 188(9): 4496-505, 2012 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-22490440

RESUMEN

Asplenic individuals are compromised not only in their ability to destroy infectious agents, but are at increased risk for death from autoimmune disease, certain tumors, and ischemic heart disease. Enhanced mortality is attributed to lack of phagocytes sequestered in spleen that efficiently engulf and destroy appropriate targets, although related cells are found elsewhere. To determine whether a unique population regulates RBC-pathogen clearance and filtration of altered self, we reviewed the anatomic literature and analyzed in situ by immunohistochemistry and immunofluorescence the expression patterns of a little-characterized cell that dominates the splenic red pulp of humans and closely related primates: the venous sinus-lining or littoral cell (LC). High expression of the formin homology domain protein 1 outlines the LC population. Although LCs are endothelial-like in distribution, they express several macrophage-directed proteins, the RBC Duffy Ag receptor for chemokines and T cell coreceptor CD8α/α, yet they lack lineage-associated markers CD34 and CD45. Strikingly, SIRPα (CD172a) expression in human spleen concentrates on LCs, consistent with recent demonstration of a key role in RBC turnover and elimination versus release of infected or altered self. Our results indicate human LCs (SIRPα(+), formin homology domain protein 1(+), CD8α/α(+), CD34(-), CD45(-)) comprise a highly plastic barrier cell population that emerged late in primate evolution coordinate with CD8 expression. Unique to Hominidae, LCs may be the ultimate determinant of which cells recirculate after passage through human spleen.


Asunto(s)
Antígenos de Diferenciación/inmunología , Proteínas Fetales/inmunología , Proteínas Nucleares/inmunología , Receptores Inmunológicos/inmunología , Bazo/inmunología , Antígenos CD/biosíntesis , Antígenos CD/inmunología , Antígenos de Diferenciación/metabolismo , Biomarcadores/metabolismo , Sistema del Grupo Sanguíneo Duffy/biosíntesis , Sistema del Grupo Sanguíneo Duffy/inmunología , Femenino , Proteínas Fetales/metabolismo , Forminas , Regulación de la Expresión Génica/inmunología , Humanos , Inmunohistoquímica , Masculino , Proteínas Nucleares/metabolismo , Receptores de Superficie Celular/biosíntesis , Receptores de Superficie Celular/inmunología , Receptores Inmunológicos/metabolismo , Bazo/citología , Bazo/metabolismo
19.
Cancer Cell ; 9(5): 379-90, 2006 May.
Artículo en Inglés | MEDLINE | ID: mdl-16697958

RESUMEN

Histiocytic sarcoma (HS) is a rare malignant proliferation of histiocytes of uncertain molecular pathogenesis. Here, genetic analysis of coincident loss of Pten and Ink4a/Arf tumor suppressors in the mouse revealed a neoplastic phenotype dominated by a premalignant expansion of biphenotypic myelolymphoid cells followed by the development of HS. Pten protein loss occurred only in the histiocytic portion of tumors, suggesting a stepwise genetic inactivation in the generation of HS. Similarly, human HS showed genetic or epigenetic inactivation of PTEN, p16(INK4A), and p14(ARF), supporting the relevance of this genetically engineered mouse model of HS. These genetic and translational observations establish a cooperative role of Pten and Ink4a/Arf in the development of HS and provide mechanistic insights into the pathogenesis of human HS.


Asunto(s)
Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Trastornos Histiocíticos Malignos/patología , Linfocitos/inmunología , Células Mieloides/inmunología , Fosfohidrolasa PTEN/metabolismo , Sarcoma/patología , Proteína p14ARF Supresora de Tumor/metabolismo , Animales , Activación Enzimática , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Trastornos Histiocíticos Malignos/inmunología , Homeostasis , Humanos , Inmunofenotipificación , Metilación , Ratones , Mutación/genética , Fosfohidrolasa PTEN/deficiencia , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sarcoma/inmunología , Proteína p14ARF Supresora de Tumor/deficiencia
20.
Hum Pathol ; 146: 28-34, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38518977

RESUMEN

Lymphocytic lobulitis (LL) is characterized by prominent lymphocytic infiltrates centered on lobules. Sclerosing lymphocytic lobulitis (SCLL) associated with diabetes mellitus (DM) or autoimmune disease (AI) was the first type to be described. Subsequently, non-sclerosing LL (NSCLL) was reported as an incidental finding in prophylactic mastectomies due to high risk germline mutations or a family history of breast cancer. The two types of LL were distinguished by stromal features and a predominant population of B-cells in the former and T-cells in the latter. In this study, 8 cases of NSCLL detected clinically or by screening were compared to 44 cases of SCLL. One case of NSCLL presented as a palpable mass, 2 as masses on screening, and 5 as MRI enhancement. In contrast, 80% of SCLL cases presented as palpable masses. Half the cases of NSCLL were associated with a BRCA1 or 2 mutation compared to 1 case of SCLL (2%). Three additional cases of NSCLL were associated with a strong family and/or personal history of breast cancer. Almost half (52%) of SCLL cases were associated with DM or AI, but only 25% of NSCLL. Immunoperoxidase studies confirmed a predominance of T-cells in NSCLL and B-cells in SCLL associated with DM or AI. It is important for pathologists to be aware of this new observation that NSCLL can be detected as a palpable mass or an imaging finding in diagnostic biopsies, as its presence can be indicative of a significant risk for breast cancer.


Asunto(s)
Linfocitos B , Neoplasias de la Mama , Linfocitos T , Humanos , Femenino , Persona de Mediana Edad , Adulto , Linfocitos B/patología , Biopsia , Linfocitos T/patología , Linfocitos T/inmunología , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Anciano , Esclerosis , Mama/patología , Mama/diagnóstico por imagen , Imagen por Resonancia Magnética , Predisposición Genética a la Enfermedad , Mutación , Enfermedades Autoinmunes/patología , Enfermedades de la Mama/patología , Enfermedades de la Mama/diagnóstico , Proteína BRCA1/genética , Proteína BRCA2/genética , Mamografía , Valor Predictivo de las Pruebas
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