RESUMO
This study reports that hairy and enhancer of split homolog-1 (HES1), known to repress gene transcription in progenitor cells of several cell lineages, was strongly expressed in cells and tissues of T-cell lymphoma expressing the oncogenic chimeric tyrosine kinase nucleophosmin (NPM)-anaplastic lymphoma kinase [ALK; ALK+ T-cell lymphoma (TCL)]. The structural analysis of the Orange domain of HES1 indicated that HES1 formed a highly stable homodimer. Of note, repression of HES1 expression led to inhibition of ALK+ TCL cell growth in vivo. The expression of the HES1 gene was induced by NPM-ALK through activation of STAT3, which bound to the gene's promoter and induced the gene's transcription. NPM-ALK also directly phosphorylated HES1 protein. In turn, HES1 up-regulated and down-regulated in ALK+ TCL cells, the expression of numerous genes, protein products of which are involved in key cell functions, such as cell proliferation and viability. Among the genes inhibited by HES1 was thioredoxin-interacting protein (TXNIP), encoding a protein implicated in promotion of cell death in various types of cells. Accordingly, ALK+ TCL cells and tissues lacked expression of TXNIP, and its transcription was co-inhibited by HES1 and STAT3 in an NPM-ALK-dependent manner. Finally, the induced expression of TXNIP induced massive apoptotic cell death of ALK+ TCL cells. The results reveal a novel NPM-ALK-controlled pro-oncogenic regulatory network and document an important role of HES and TXNIP in the NPM-ALK-driven oncogenesis, with the former protein displaying oncogenic and the latter tumor suppressor properties.
Assuntos
Quinase do Linfoma Anaplásico , Proteínas de Transporte , Linfoma de Células T , Fatores de Transcrição HES-1 , Quinase do Linfoma Anaplásico/genética , Carcinogênese/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Humanos , Linfoma de Células T/genética , Linfoma de Células T/metabolismo , Linfoma de Células T/patologia , Oncogenes , Fosforilação , Fatores de Transcrição HES-1/genética , Fatores de Transcrição HES-1/metabolismoRESUMO
We conducted a phase I/II multicenter trial using 6 cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients with CD30-positive (+) B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22 with primary mediastinal B-cell lymphoma (PMBCL), 5 with diffuse large B-cell lymphoma (DLBCL), and 2 with gray zone lymphoma (GZL). There were no treatment-related deaths; 32% of patients had non-hematological grade 3/4 toxicities. The overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving complete response at the end of systemic treatment. Consolidative radiation following end of treatment response assessment was permissible and used in 52% of all patients including 59% of patients with PMBCL. With a median follow-up of 30 months, the 2-year progression-free survival (PFS) and overall survival (OS) were 85% (95% CI: 66-94) and 100%, respectively. In the PMBCL cohort, 2-year PFS was 86% (95% CI: 62-95). In summary, BV-R-CHP with or without consolidative radiation is a feasible and active frontline regimen for CD30+ B-cell lymphomas (NCT01994850).
Assuntos
Imunoconjugados , Linfoma Difuso de Grandes Células B , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Brentuximab Vedotin , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Imunoconjugados/uso terapêutico , Antígeno Ki-1 , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Prednisona/uso terapêutico , Rituximab/uso terapêutico , Resultado do Tratamento , Vincristina/uso terapêuticoAssuntos
Transdiferenciação Celular , Imunoterapia/efeitos adversos , Linfoma de Célula do Manto/terapia , Segunda Neoplasia Primária/etiologia , Sarcoma/etiologia , Adenina/administração & dosagem , Adenina/efeitos adversos , Adenina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transdiferenciação Celular/genética , Transdiferenciação Celular/imunologia , Reprogramação Celular/genética , Reprogramação Celular/imunologia , Reprogramação Celular/fisiologia , Terapia Combinada , Epigênese Genética/fisiologia , Epigenoma/imunologia , Rearranjo Gênico , Genes de Cadeia Pesada de Imunoglobulina/genética , Humanos , Imunoterapia/métodos , Linfonodos/patologia , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/imunologia , Segunda Neoplasia Primária/diagnóstico , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Receptores de Antígenos de Linfócitos T/uso terapêutico , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Sarcoma/genética , Sarcoma/imunologia , Sarcoma/patologia , Transplante Autólogo/efeitos adversos , Células Tumorais CultivadasRESUMO
The genetic and molecular abnormalities underlying histological transformation (HT) of nodal marginal zone lymphoma (NMZL) to diffuse large B-cell lymphoma (DLBCL) are not well known. While del(20q12) is commonly deleted in myelodysplastic syndrome it has not previously been associated with DLBCL. We recently described a case of DLBCL harboring del(20q12) in a patient with a history of MZL involving lymph nodes and skin. Here we report eight matched cases of transformed MZL(tMZL): six from nodal MZL (tNMZL) and two from splenic MZL (tSMZL). We found >20% del(20q12) in 4/6 tNMZL, but not in tSMZL, nor in unmatched DLBCL, MZL with increased large cells (MZL-ILC), or MZL cases. To examine whether transformation is associated with a specific gene signature, the matched cases were analyzed for multiplexed gene expression using the Nanostring PanCancer Pathways panel. The differential gene expression signature revealed enrichment of inflammatory markers, as previously observed in MZL. Also, tMZL and de novo DLBCL were enriched for extracellular matrix proteins such as collagen and fibronectin, vascular development protein PDGFRß, DNA repair protein RAD51, and oncogenic secrete protein Wnt11. A subset of genes is expressed differentially in del(20q12) tMZL cases vs non-del(20q12) tMZL cases. These results suggest a specific pathway is involved in the histological transformation of NMZL, which could serve as an indicator of aggressive clinical course in this otherwise indolent neoplasm.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 20/genética , Regulação Neoplásica da Expressão Gênica , Linfoma de Zona Marginal Tipo Células B , Linfoma Difuso de Grandes Células B , Proteínas de Neoplasias , Neoplasias Cutâneas , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma de Zona Marginal Tipo Células B/metabolismo , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologiaRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/genética , Morfolinas/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Rearranjo Gênico , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Translocação GenéticaRESUMO
Rosai-Dorfman disease (RDD) is an enigmatic histiocytic disorder classically diagnosed by a distinctive combination of pathological features: emperipolesis, or migration of intact haematological cells through the voluminous cytoplasm of lesional histiocytes, and expression of S100 by these histiocytes. The pathogenesis has long been elusive until the recent detection of recurrent and mutually exclusive mutations in several oncogenes in the mitogen-activated protein kinase (MAPK) pathway. Based on these findings, we investigated a cohort of 21 RDD patients and found that the lesional histiocytes in 86% (18/21) of patients exhibited strong and diffuse nuclear Cyclin D1 expression, which not only may provide a diagnostic marker for this sometimes pathologically challenging disease, but also probably reflects constitutive MAPK pathway activation because we additionally identified phosphorylated-ERK expression in 90% (19/21) of cases. Further, we performed massively parallel sequencing on a subset (6/18) of the CyclinD1 positive cases, identifying several mutations that have not been previously reported in RDD. Taken together, our findings bolster the concept of RDD as a disease of MAPK activation in a substantial percentage of cases and enhance the current understanding of the pathogenesis of RDD.
Assuntos
Núcleo Celular , Ciclina D1 , Regulação da Expressão Gênica , Histiocitose Sinusal , Sistema de Sinalização das MAP Quinases/genética , Mutação , Adulto , Idoso , Núcleo Celular/genética , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Ciclina D1/biossíntese , Ciclina D1/genética , Feminino , Histiocitose Sinusal/genética , Histiocitose Sinusal/metabolismo , Histiocitose Sinusal/patologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Therapeutic targeting of initiating oncogenes is the mainstay of precision medicine. Considerable efforts have been expended toward silencing MYC, which drives many human cancers including Burkitt lymphomas (BL). Yet, the effects of MYC silencing on standard-of-care therapies are poorly understood. Here we found that inhibition of MYC transcription renders B-lymphoblastoid cells refractory to chemotherapeutic agents. This suggested that in the context of chemotherapy, stabilization of Myc protein could be more beneficial than its inactivation. We tested this hypothesis by pharmacologically inhibiting glycogen synthase kinase 3ß (GSK-3ß), which normally targets Myc for proteasomal degradation. We discovered that chemorefractory BL cell lines responded better to doxorubicin and other anti-cancer drugs when Myc was transiently stabilized. In vivo, GSK3 inhibitors (GSK3i) enhanced doxorubicin-induced apoptosis in BL patient-derived xenografts (BL-PDX), as well as in murine MYC-driven lymphoma allografts. This enhancement was accompanied by and required deregulation of several key genes acting in the extrinsic, death-receptor-mediated apoptotic pathway. Consistent with this mechanism of action, GSK3i also facilitated lymphoma cell killing by a death ligand TRAIL and by a death receptor agonist mapatumumab. Thus, GSK3i synergizes with both standard chemotherapeutics and direct engagers of death receptors and could improve outcomes in patients with refractory lymphomas.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linfoma de Células B/tratamento farmacológico , Proteínas Proto-Oncogênicas c-myc/metabolismo , Animais , Linfoma de Burkitt/tratamento farmacológico , Linfoma de Burkitt/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Linfoma de Células B/metabolismo , Masculino , Camundongos , Transdução de SinaisAssuntos
Antineoplásicos/uso terapêutico , Genes bcl-2 , Genes myc , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/genética , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adenina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Biomarcadores Tumorais , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Linfoma de Células B/diagnóstico , Linfoma de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Piperidinas , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Recidiva , Retratamento , Resultado do TratamentoRESUMO
BACKGROUND: Extranodal NK/T-cell lymphoma, nasal type (ENKTCL-NT), is a rare aggressive subtype of non-Hodgkin lymphoma characterized by angioinvasion, angiodestruction, necrosis and strong association with Epstein-Barr virus (EBV). ENKTCL-NT occurs worldwide and is more prevalent in Asian and the Native American populations of Mexico, Central and South America. It represents approximately 10% of all peripheral T-cell lymphomas worldwide. The aim of this report is to present a rare case of ENKTCL-NT with an unusually indolent clinical course and low-grade histopathologic features. CASE PRESENTATION: A 71-year-old Asian woman with a long-standing history of seasonal rhinosinusitis presented with persistent nasal congestion, cough, and fever unresponsive to antihistamines and antibiotics. Histopathological evaluation of a polypoid nasal mass revealed an atypical infiltrate with predominantly small lymphoid cells that were CD2+, surface CD3-, cytoplasmic CD3+, CD5(dim)+, CD7(dim)+, cytotoxic markers (granzyme B and perforin)+, EBER+ and CD56-. The Ki-67 proliferative index was very low (< 1%). T-cell receptor gamma gene rearrangement studies were positive for a monoclonal rearrangement, and sequencing studies identified a novel KIT mutation (p. K167 M, c. 500 A > T). A diagnosis of low-grade ENKTCL-NT was rendered. CONCLUSIONS: Our case of ENKTCL-NT is unusual due to (1) an indolent clinical course (2) low-grade histopathologic features including a low proliferative index (3) lack of CD56 expression and (4) a novel KIT mutation. This case raises awareness of the existence of a subset of cases of ENKTCL-NT that can potentially be misdiagnosed as a reactive process, particularly in patients with recurrent chronic rhinosinusitis.
Assuntos
Biomarcadores Tumorais/genética , Linfoma Extranodal de Células T-NK/genética , Mutação , Neoplasias Nasais/genética , Proteínas Proto-Oncogênicas c-kit/genética , Rinite Alérgica Sazonal/complicações , Sinusite/complicações , Idoso , Biópsia , Doença Crônica , Diagnóstico Diferencial , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Linfoma Extranodal de Células T-NK/complicações , Linfoma Extranodal de Células T-NK/patologia , Linfoma Extranodal de Células T-NK/cirurgia , Gradação de Tumores , Neoplasias Nasais/complicações , Neoplasias Nasais/patologia , Neoplasias Nasais/cirurgia , Fenótipo , Valor Preditivo dos Testes , Rinite Alérgica Sazonal/diagnóstico , Sinusite/diagnósticoRESUMO
Posttransplant lymphoproliferative disorders (PTLDs) are a diverse group of lymphoid or plasmacytic proliferations frequently driven by Epstein-Barr virus (EBV). EBV-negative PTLDs appear to represent a distinct entity. This report describes an unusual case of a 33-year-old woman that developed a monomorphic EBV-negative PTLD consistent with diffuse large B-cell lymphoma (DLBCL) 13 years after heart-lung transplant. Histological examination revealed marked pleomorphism of the malignant cells including nodular areas reminiscent of classical Hodgkin lymphoma (cHL) with abundant large, bizarre Hodgkin-like cells. By immunostaining, the malignant cells were immunoreactive for CD45, CD20, CD79a, PAX5, BCL6, MUM1, and p53 and negative for CD15, CD30, latent membrane protein 1 (LMP1), and EBV-encoded RNA (EBER). Flow cytometry demonstrated lambda light chain restricted CD5 and CD10 negative B-cells. Fluorescence in situ hybridization studies (FISH) were negative for cMYC, BCL2, and BCL6 rearrangements but showed deletion of TP53 and monosomy of chromosome 17. Next-generation sequencing studies (NGS) revealed numerous genetic alterations including 6 pathogenic mutations in ASXL1, BCOR, CDKN2A, NF1, and TP53(x2) genes and 30 variants of unknown significance (VOUS) in ABL1, ASXL1, ATM, BCOR, BCORL1, BRNIP3, CDH2, CDKN2A, DNMT3A, ETV6, EZH2, FBXW7, KIT, NF1, RUNX1, SETPB1, SF1, SMC1A, STAG2, TET2, TP53, and U2AF2.
RESUMO
B-cell receptor (BCR)-mediated signaling plays an important role in the pathogenesis of a subset of diffuse large B-cell lymphoma (DLBCL), and novel agents targeting this pathway are now in clinical use. We have previously identified a signature of active BCR signaling on formalin-fixed paraffin-embedded specimens using quantitative immunofluorescence, allowing for identification of patients who might benefit from anti-BCR therapies. We sought to characterize the clinicopathologic significance of active BCR signaling in DLBCL by correlating measures of signaling intensity with clinical features and various tumor cell characteristics. High MYC and concurrent high MYC and BCL2 double-expression was positively correlated with individual markers of active BCR signaling and cases with MYC/BCL2 double-expression showed overall greater BCR activation compared to cases lacking double-expression. Our findings suggest that the BCR signaling pathway may be more active in MYC/BCL2 double-expressor DLBCL and may represent a rational therapeutic target in this aggressive DLBCL subgroup.
Assuntos
Linfócitos B/metabolismo , Regulação Neoplásica da Expressão Gênica , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução de Sinais , Feminino , Imunofluorescência , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) typically leads to effacement of the nodal architecture by an infiltrate of malignant cells. Rarely (<1%), DLBCL can present with an interfollicular pattern (DLBCL-IF) preserving the lymphoid follicles. It has been postulated that DLBCL-IF is derived from marginal zone B cells and may represent a large-cell transformation of marginal zone lymphoma (MZL), however no direct evidence has been provided to date. Here we describe a rare case of a diagnostically challenging DLBCL-IF involving a lymph node in a patient with a prior history of lymphadenopathy for several years and MZL involving skin. CASE PRESENTATION: A 53-year old man presented to our Dermatology Clinic due to a 1-year history of generalized itching, fatigue of 2-3 month's duration, nausea and mid back rash that was biopsied. PET (positron emission tomography)/CT (computed tomography) was performed and revealed inguinal, pelvic, retroperitoneal, axillary, and cervical lymphadenopathy. The patient was referred to surgery for excisional biopsy of a right inguinal lymph node. Diagnostic H&E stained slides and ancillary studies were reviewed for the lymph node and skin specimens. B-cell clonality by PCR and sequencing studies were performed on both specimens. We demonstrate that this patient's MZL and DLBCL-IF are clonally related, strongly suggesting that transformation of MZL to DLBCL had occurred. Furthermore, we identified a novel deletion of the long arm of chromosome 20 (del(20q12)) and a missense mutation in BIRC3 (Baculoviral IAP repeat-containing protein 3) in this patient's DLBCL that are absent from his MZL, suggesting that these genetic alterations contributed to the large cell transformation. CONCLUSIONS: To our knowledge, this is the first report providing molecular evidence for a previously suspected link between MZL and DLBCL-IF. In addition, we describe for the first time del(20q12) and a missense mutation in BIRC3 in DLBCL. Our findings also raise awareness of DLBCL-IF and discuss the diagnostic pitfalls of this rare entity.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 20/genética , Proteínas Inibidoras de Apoptose/genética , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma Difuso de Grandes Células B/patologia , Mutação de Sentido Incorreto , Ubiquitina-Proteína Ligases/genética , Proteína 3 com Repetições IAP de Baculovírus , Biomarcadores Tumorais/análise , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma Difuso de Grandes Células B/genética , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da PolimeraseRESUMO
Diffuse large B-cell lymphoma is extranodal in approximately 40% of cases, arising in nearly any organ system. DLBCL involvement of soft tissue and in particular skeletal muscle is extremely rare, comprising less than 1% of all extranodal non-Hodgkin lymphomas (NHL). We report a case of a 79-year-old man that presented with a DLBCL of the left triceps. In particular, we describe an unusual histologic appearance of pseudoglandular structures, resembling adenocarcinoma. We performed a review of lymphoma cases involving skeletal muscle diagnosed at our institution over the past 15 years as well as thorough PubMed review of the literature. We discuss the features of lymphoma involving skeletal muscle as it pertains to clinical characteristics, histologic subtype, tumor localization, diagnostic studies, therapy, and outcome. Finally, we highlight the diagnostic difficulties that can present in these rare and often challenging cases.
RESUMO
Small B-cell lymphomas and leukemias (SBCLs) are a clinically, morphologically, immunophenotypically and genetically heterogeneous group of clonal lymphoid neoplasms, including entities such as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), lymphoplasmacytic lymphoma (LPL), marginal zone lymphoma (MZL) and hairy cell leukemia (HCL). The pathogenesis of some of these lymphoid malignancies is characterized by distinct translocations, for example t(11;14) in the majority of cases of MCL and t(14;18) in most cases of FL, whereas other entities are associated with a variety of recurrent but nonspecific numeric chromosomal abnormalities, as exemplified by del(13q14), del(11q22), and +12 in CLL, and yet others such as LPL and HCL that lack recurrent or specific cytogenetic aberrations. The recent surge in next generation sequencing (NGS) technology has shed more light on the genetic landscape of SBCLs through characterization of numerous driver mutations including SF3B1 and NOTCH1 in CLL, ATM and CCND1 in MCL, KMT2D and EPHA7 in FL, MYD88 (L265P) in LPL, KLF2 and NOTCH2 in splenic MZL (SMZL) and BRAF (V600E) in HCL. The identification of distinct genetic lesions not only provides greater insight into the molecular pathogenesis of these disorders but also identifies potential valuable biomarkers for prognostic stratification, as well as specific targets for directed therapy. This review discusses the well-established and recently identified molecular lesions underlying the pathogenesis of SBCLs, highlights their clinical relevance and summarizes novel targeted therapies.
Assuntos
Aberrações Cromossômicas , Leucemia de Células B/genética , Linfoma de Células B/genética , Biomarcadores Tumorais , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Leucemia de Células B/diagnóstico , Leucemia de Células B/metabolismo , Leucemia de Células B/terapia , Linfoma de Células B/diagnóstico , Linfoma de Células B/metabolismo , Linfoma de Células B/terapia , Terapia de Alvo Molecular , Mutação , Transdução de Sinais/efeitos dos fármacosRESUMO
Initial identification of chronic myelogenous leukemia is very important since targeted therapy leads to life-saving remission. Rarely, chronic myelogenous leukemia presents with an unusual picture, making the diagnosis challenging. We describe such a case of chronic myelogenous leukemia in blast crisis in a previously healthy 61-year-old woman. The patient presented with fever, myalgias, and night sweats and was first worked up for an infectious etiology. Because of persistent anemia, a bone marrow biopsy was performed that revealed fibrosis with increased megakaryoblasts. Even though initial cytogenetic studies could not be performed because of "dry tap" aspirate, persistent efforts for cytogenetic studies were made, including a "squeeze preparation" from the core biopsy, which revealed t(9;22)(q34;q11.2) and trisomy 19. The patient was treated with tyrosine kinase inhibitors, chemotherapy, and subsequently an allogeneic stem cell transplant. She is in persistent remission. This case illustrates a complex presentation of chronic myelogenous leukemia and provides an overview of morphologic cues and the importance of performing cytogenetic studies that led to the diagnosis.
Assuntos
Cromossomos Humanos Par 19 , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Trissomia , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Células Progenitoras de Megacariócitos/patologia , Pessoa de Meia-Idade , Cromossomo Filadélfia , Mielofibrose Primária/patologiaRESUMO
B cell receptor (BCR) signaling pathway components represent promising treatment targets in diffuse large B cell lymphoma (DLBCL) and additional B cell tumors. BCR signaling activates spleen tyrosine kinase (SYK) and downstream pathways including PI3K/AKT and NF-κB. In previous studies, chemical SYK blockade selectively decreased BCR signaling and induced apoptosis of BCR-dependent DLBCLs. Herein, we characterize distinct SYK/PI3K-dependent survival pathways in DLBCLs with high or low baseline NF-κB activity including selective repression of the pro-apoptotic HRK protein in NF-κB-low tumors. We also define SYK/PI3K-dependent cholesterol biosynthesis as a feed-forward mechanism of maintaining the integrity of BCRs in lipid rafts in DLBCLs with low or high NF-κB. In addition, SYK amplification and PTEN deletion are identified as selective genetic alterations in primary "BCR"-type DLBCLs.