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ABSTRACT: Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is considered the standard-of-care for patients with advanced-stage diffuse large B-cell lymphoma (DLBCL), despite findings that patients with nongerminal center B-cell like (non-GCB) have significantly worse outcome with this regimen. We evaluated the prognostic significance of baseline risk factors, including cell of origin (COO) classified by the Hans algorithm, within an alternative chemoimmunotherapy program. At Memorial Sloan Kettering Cancer Center (MSK), 151 patients with DLBCL received sequential R-CHOP induction and (R)-ICE (rituximab, ifosfamide, carboplatin, and etoposide) consolidation. Outcome analysis based on COO was validated with a propensity score-matched cohort treated with R-CHOP from the Mayo Clinic component of the Molecular Epidemiology Resource (MER). Among the patients with GCB (n = 69) and non-GCB (n = 69) at MSK, event-free survival (EFS) of non-GCB was superior to that of GCB (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.29-0.98). Overall survival (OS) demonstrated an association in the same direction but was not statistically significant (HR, 0.68; 95% CI, 0.33-1.42). Propensity score-matched patients from MSK (n = 108) demonstrated a small attenuation in the HRs for EFS (HR, 0.57; 95% CI, 0.27-1.18) and OS (HR, 0.76; 95% CI, 0.33-1.79) and were no longer statistically significant. In contrast, the matched MER cohort (n = 108) demonstrated an EFS association (HR, 1.17; 95% CI, 0.70-1.95) and OS association (HR, 1.13; 95% CI, 0.64-2.00) in the opposite direction, but were also not statistically significant. R-CHOP induction and (R)-ICE consolidation may overcome the negative prognostic impact of the non-GCB phenotype, per the Hans algorithm, and can be preferentially selected for this population. This trial was registered at www.ClinicalTrials.gov as #NCT00039195 and #NCT00712582.
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Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida , Doxorrubicina , Ifosfamida , Linfoma de Células B Grandes Difuso , Prednisona , Rituximab , Vincristina , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/uso terapéutico , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Etopósido/uso terapéutico , Ifosfamida/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/mortalidad , Prednisona/uso terapéutico , Pronóstico , Rituximab/uso terapéutico , Resultado del Tratamiento , Vincristina/uso terapéutico , Estudios de Casos y ControlesRESUMEN
Myelodysplastic syndrome (MDS) is characterized by ineffective hematopoiesis with morphologic dysplasia and a propensity to transform into overt acute myeloid leukemia (AML). Our analysis of two cohorts of 20 MDS and 49 AML with multi-lineage dysplasia patients shows a reduction in Nucleophosmin 1 (NPM1) expression in 70% and 90% of cases, respectively. A mouse model of Npm1 conditional knockout (cKO) in hematopoietic cells reveals that Npm1 loss causes premature aging of hematopoietic stem cells (HSCs). Mitochondrial activation in Npm1-deficient HSCs leads to aberrant activation of the NLRP3 inflammasome, which correlates with a developing MDS-like phenotype. Npm1 cKO mice exhibit shortened survival times, and expansion of both the intra- and extra-medullary myeloid populations, while evoking a p53-dependent response. After transfer into a p53 mutant background, the resulting Npm1/p53 double KO mice develop fatal leukemia within 6 months. Our findings identify NPM1 as a regulator of HSC aging and inflammation and highlight the role of p53 in MDS progression to leukemia.
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Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Envejecimiento/genética , Animales , Células Madre Hematopoyéticas/metabolismo , Humanos , Inflamación/genética , Inflamación/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Ratones , Mutación , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Nucleofosmina , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Mutations in splicing factors (SF) are the predominant class of mutations in myelodysplastic syndrome (MDS), but convergent downstream disease drivers remain elusive. To identify common direct targets of missplicing by mutant U2AF1 and SRSF2, we performed RNA sequencing and enhanced version of the cross-linking and immunoprecipitation assay in human hematopoietic stem/progenitor cells derived from isogenic induced pluripotent stem cell (iPSC) models. Integrative analyses of alternative splicing and differential binding converged on a long isoform of GNAS (GNAS-L), promoted by both mutant factors. MDS population genetics, functional and biochemical analyses support that GNAS-L is a driver of MDS and encodes a hyperactive long form of the stimulatory G protein alpha subunit, Gαs-L, that activates ERK/MAPK signaling. SF-mutant MDS cells have activated ERK signaling and consequently are sensitive to MEK inhibitors. Our findings highlight an unexpected and unifying mechanism by which SRSF2 and U2AF1 mutations drive oncogenesis with potential therapeutic implications for MDS and other SF-mutant neoplasms. SIGNIFICANCE: SF mutations are disease-defining in MDS, but their critical effectors remain unknown. We discover the first direct target of convergent missplicing by mutant U2AF1 and SRSF2, a long GNAS isoform, which activates G protein and ERK/MAPK signaling, thereby driving MDS and rendering mutant cells sensitive to MEK inhibition. This article is highlighted in the In This Issue feature, p. 587.
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Síndromes Mielodisplásicos , Neoplasias , Empalme Alternativo , Cromograninas/genética , Cromograninas/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Subunidades alfa de la Proteína de Unión al GTP Gs/metabolismo , Humanos , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Mutación , Síndromes Mielodisplásicos/genética , ARN/metabolismo , Empalme del ARN , Factores de Empalme de ARN/genética , Factores de Empalme Serina-Arginina/metabolismo , Factor de Empalme U2AF/genética , Factor de Empalme U2AF/metabolismoRESUMEN
B-cell maturation antigen (BCMA) is a prominent tumor-associated target for chimeric antigen receptor (CAR)-T cell therapy in multiple myeloma (MM). Here, we describe the case of a patient with MM who was enrolled in the CARTITUDE-1 trial ( NCT03548207 ) and who developed a progressive movement disorder with features of parkinsonism approximately 3 months after ciltacabtagene autoleucel BCMA-targeted CAR-T cell infusion, associated with CAR-T cell persistence in the blood and cerebrospinal fluid, and basal ganglia lymphocytic infiltration. We show BCMA expression on neurons and astrocytes in the patient's basal ganglia. Public transcriptomic datasets further confirm BCMA RNA expression in the caudate of normal human brains, suggesting that this might be an on-target effect of anti-BCMA therapy. Given reports of three patients with grade 3 or higher parkinsonism on the phase 2 ciltacabtagene autoleucel trial and of grade 3 parkinsonism in the idecabtagene vicleucel package insert, our findings support close neurological monitoring of patients on BCMA-targeted T cell therapies.
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Antígeno de Maduración de Linfocitos B/inmunología , Inmunoterapia Adoptiva/métodos , Trastornos del Movimiento/terapia , Trastornos Parkinsonianos/terapia , Receptores Quiméricos de Antígenos/inmunología , HumanosRESUMEN
Fifty percent of diffuse large B cell lymphoma (DLBCL) cases lack cell-surface expression of the class I major histocompatibility complex (MHC-I), thus escaping recognition by cytotoxic T cells. Here we show that, across B cell lymphomas, loss of MHC-I, but not MHC-II, is preferentially restricted to DLBCL. To identify the involved mechanisms, we performed whole exome and targeted HLA deep-sequencing in 74 DLBCL samples, and found somatic inactivation of B2M and the HLA-I loci in 80% (34 of 42) of MHC-INEG tumors. Furthermore, 70% (22 of 32) of MHC-IPOS DLBCLs harbored monoallelic HLA-I genetic alterations (MHC-IPOS/mono), indicating allele-specific inactivation. MHC-INEG and MHC-IPOS/mono cases harbored significantly higher mutational burden and inferred neoantigen load, suggesting potential coselection of HLA-I loss and sustained neoantigen production. Notably, the analysis of >500,000 individuals across different cancer types revealed common germline HLA-I homozygosity, preferentially in DLBCL. In mice, germinal-center B cells lacking HLA-I expression did not progress to lymphoma and were counterselected in the context of oncogene-driven lymphomagenesis, suggesting that additional events are needed to license immune evasion. These results suggest a multistep process of HLA-I loss in DLBCL development including both germline and somatic events, and have direct implications for the pathogenesis and immunotherapeutic targeting of this disease.
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Transformación Celular Neoplásica/genética , Antígenos de Histocompatibilidad Clase I/genética , Linfoma de Células B Grandes Difuso/genética , Línea Celular Tumoral , Citidina Desaminasa , Silenciador del Gen , Humanos , Linfoma de Células B Grandes Difuso/inmunología , Proteínas Proto-Oncogénicas c-bcl-6/genética , Microglobulina beta-2/genéticaRESUMEN
Hematopathology fellowship education has grown in complexity as patient-centered treatment plans have come to depend on integration of clinical, morphologic, immunophenotypic, molecular, and cytogenetic variables. This complexity is in competition with the need for timely hematopathology care with stewardship of patient, laboratory, and societal resources. Accreditation Council for Graduate Medical Education Milestones provide a guidance document for hematopathology training, but fellows and their educators are in need of a simple framework that allows assessment and feedback of growth toward independent hematopathology practice. Entrustable professional activities provide one such framework, and herein, we provide proposed Hematopathology Fellowship Entrustable Professional Activities based on review of pertinent guidelines and literature, with multiple rounds of expert and stakeholder input utilizing a modified mini-Delphi approach. Ten core entrustable professional activities deemed essential for graduating hematopathology fellows were developed together with skills and knowledge statements, example scenarios, and corresponding Accreditation Council for Graduate Medical Education Milestones. Application of these entrustable professional activities in program design, fellow evaluation, and decisions regarding level of supervision is discussed with consideration of benefits and barriers to implementation. These entrustable professional activities may be used by hematopathology fellowship directors and faculty to provide fellows with timely constructive feedback, determine entrustment decisions, provide the Clinical Competency Committee with granular data to support Milestone evaluations, and provide insight into areas of potential improvement in fellowship training. Fellows will benefit from a clear roadmap to independent hematopathology practice with concrete and timely feedback.
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BACKGROUND & AIMS: Tufting enteropathy (TE) is a rare congenital disorder often caused by mutations in the gene encoding epithelial cell adhesion molecule (EpCam). The disease leads to diarrhoea, intestinal failure and dependence on total parenteral nutrition (TPN). These patients often have liver impairments, but the pathology and mechanism of the damage are not well understood. We evaluated liver biopsies from TE patients to understand the pathophysiology. METHODS: We identified three patients with TE who underwent liver biopsy. Two normal controls and 45 patients on TPN secondary to short gut syndrome were selected for comparison (five were age- and TPN duration matched to the TE patients). RESULTS: We found that all TE patients showed a complete loss of EpCam expression in enterocytes and biliary epithelial cells, while the normal and TPN groups show basolateral expression. Histologically TE patients showed ductopenia, which was not seen in control groups. E-cadherin and ß-catenin are normally located along the lateral membrane of biliary epithelial cells. However, they were relocated to the apical membrane in TE patients, indicating a defect in the apical-basal polarity of cholangiocytes. We examined hepatic reparative cells and found near absence of hepatic progenitor cells and intermediate hepatobiliary cells with mild reactive ductular cells in TE patients. CONCLUSION: Our findings show that TE is associated with disrupted polarity of cholangiocyte and ductopenia. We demonstrate for the first time a role of EpCam in the maintenance of integrity of biliary epithelium. We also provided evidence for a disrupted development of hepatic reparative cells.
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Diarrea Infantil , Síndromes de Malabsorción , Molécula de Adhesión Celular Epitelial , Epitelio , Humanos , IntestinosRESUMEN
OBJECTIVE: To describe a case of Burkitt lymphoma (BL) in a child manifesting with acute airway obstruction. To review available literature on the clinical features and characteristic presentation of this disease. METHODS: Case report with literature review. RESULTS: We present the case of an 8-year-old boy with nasopharyngeal BL manifesting initially as sore throat, nasal congestion, and snoring that progressed to dyspnea and, ultimately, acute airway obstruction requiring emergent tracheostomy. The child was treated with intensive chemotherapy and achieved complete response. CONCLUSION: This case highlights the importance of maintaining high clinical suspicion when evaluating common otolaryngologic symptoms and emphasizes the potential for Burkitt lymphoma to cause rapid patient deterioration.
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Obstrucción de las Vías Aéreas/etiología , Obstrucción de las Vías Aéreas/cirugía , Linfoma de Burkitt/complicaciones , Linfoma de Burkitt/tratamiento farmacológico , Neoplasias Nasofaríngeas/complicaciones , Neoplasias Nasofaríngeas/tratamiento farmacológico , Traqueostomía/métodos , Enfermedad Aguda , Obstrucción de las Vías Aéreas/diagnóstico por imagen , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/diagnóstico por imagen , Niño , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Disnea/diagnóstico por imagen , Disnea/etiología , Disnea/cirugía , Detección Precoz del Cáncer , Urgencias Médicas , Humanos , Masculino , Metotrexato/administración & dosificación , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/diagnóstico por imagen , Tomografía de Emisión de Positrones , Prednisona/administración & dosificación , Rituximab/administración & dosificación , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Vincristina/administración & dosificaciónAsunto(s)
Betacoronavirus/patogenicidad , Infecciones por Coronavirus/virología , Linfocitos/citología , Neumonía Viral/virología , Síndrome Respiratorio Agudo Grave/virología , COVID-19 , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/patología , Humanos , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/patología , SARS-CoV-2 , Síndrome Respiratorio Agudo Grave/diagnósticoAsunto(s)
Betacoronavirus/aislamiento & purificación , Infecciones por Coronavirus/patología , Granulocitos/patología , Neumonía Viral/patología , Anciano , COVID-19 , Enfermedad de la Arteria Coronaria/complicaciones , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Granulocitos/virología , Humanos , Hipoxia/complicaciones , Fallo Renal Crónico/complicaciones , Recuento de Leucocitos , Leucocitosis/sangre , Leucocitosis/complicaciones , Leucocitosis/patología , Masculino , Pandemias , Neumonía Viral/sangre , Neumonía Viral/complicaciones , SARS-CoV-2Asunto(s)
Regulación Neoplásica de la Expresión Génica , Mieloma Múltiple/metabolismo , Neoplasias de los Músculos/metabolismo , Proteínas de Neoplasias/biosíntesis , Receptores CXCR4/biosíntesis , Transducción de Señal , Anciano , Humanos , Masculino , Mieloma Múltiple/patología , Mieloma Múltiple/terapia , Neoplasias de los Músculos/patología , Neoplasias de los Músculos/secundario , Neoplasias de los Músculos/terapia , Invasividad NeoplásicaRESUMEN
We report a case of a relapsed hemophagocytic intramedullary plasmacytoma, previously non-phagocytic, in conjunction with development of a new clone with different cytogenetic abnormalities forming a solitary plasmacytoma.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/terapia , Plasmacitoma/diagnóstico , Plasmacitoma/terapia , Adulto , Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Biomarcadores de Tumor , Neoplasias Óseas/patología , Bortezomib/administración & dosificación , Carmustina/administración & dosificación , Cisplatino/administración & dosificación , Ciclofosfamida/administración & dosificación , Citarabina/administración & dosificación , Dexametasona/administración & dosificación , Doxorrubicina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Humanos , Imagen por Resonancia Magnética , Melfalán/administración & dosificación , Recurrencia Local de Neoplasia , Oligopéptidos/administración & dosificación , Plasmacitoma/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones , Hueso Púbico , Enfermedades Raras , Trasplante de Células Madre , Talidomida/administración & dosificación , Trasplante Autólogo , Resultado del TratamientoAsunto(s)
Centro Germinal/metabolismo , Linfoma de Células B Grandes Difuso/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Factores de Transcripción Forkhead/metabolismo , Centro Germinal/patología , Humanos , Inmunohistoquímica , Factores Reguladores del Interferón/metabolismo , Proteínas con Dominio LIM/metabolismo , Linfoma de Células B Grandes Difuso/patología , Factores de Transcripción MEF2/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Represoras/metabolismo , Serpinas/metabolismoRESUMEN
BACKGROUNDAdoptive transfer of donor-derived EBV-specific cytotoxic T-lymphocytes (EBV-CTLs) can eradicate EBV-associated lymphomas (EBV-PTLD) after transplantation of hematopoietic cell (HCT) or solid organ (SOT) but is unavailable for most patients.METHODSWe developed a third-party, allogeneic, off-the-shelf bank of 330 GMP-grade EBV-CTL lines from specifically consented healthy HCT donors. We treated 46 recipients of HCT (n = 33) or SOT (n = 13) with established EBV-PTLD, who had failed rituximab therapy, with third-party EBV-CTLs. Treatment cycles consisted of 3 weekly infusions of EBV-CTLs and 3 weeks of observation.RESULTSEBV-CTLs did not induce significant toxicities. One patient developed grade I skin graft-versus-host disease. Complete remission (CR) or sustained partial remission (PR) was achieved in 68% of HCT recipients and 54% of SOT recipients. For patients who achieved CR/PR or stable disease after cycle 1, one year overall survival was 88.9% and 81.8%, respectively. In addition, 3 of 5 recipients with POD after a first cycle who received EBV-CTLs from a different donor achieved CR or durable PR (60%) and survived longer than 1 year. Maximal responses were achieved after a median of 2 cycles.CONCLUSIONThird-party EBV-CTLs of defined HLA restriction provide safe, immediately accessible treatment for EBV-PTLD. Secondary treatment with EBV-CTLs restricted by a different HLA allele (switch therapy) can also induce remissions if initial EBV-CTLs are ineffective. These results suggest a promising potential therapy for patients with rituximab-refractory EBV-associated lymphoma after transplantation.TRIAL REGISTRATIONPhase II protocols (NCT01498484 and NCT00002663) were approved by the Institutional Review Board at Memorial Sloan Kettering Cancer Center, the FDA, and the National Marrow Donor Program.FUNDINGThis work was supported by NIH grants CA23766 and R21CA162002, the Aubrey Fund, the Claire Tow Foundation, the Major Family Foundation, the Max Cure Foundation, the Richard "Rick" J. Eisemann Pediatric Research Fund, the Banbury Foundation, the Edith Robertson Foundation, and the Larry Smead Foundation. Atara Biotherapeutics licensed the bank of third-party EBV-CTLs from Memorial Sloan Kettering Cancer Center in June 2015.
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Traslado Adoptivo , Infecciones por Virus de Epstein-Barr , Trasplante de Células Madre Hematopoyéticas , Herpesvirus Humano 4/inmunología , Linfoma , Rituximab/administración & dosificación , Linfocitos T/inmunología , Adulto , Aloinjertos , Supervivencia sin Enfermedad , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/mortalidad , Infecciones por Virus de Epstein-Barr/terapia , Femenino , Humanos , Linfoma/inmunología , Linfoma/mortalidad , Linfoma/terapia , Linfoma/virología , Masculino , Tasa de Supervivencia , Linfocitos T/patologíaAsunto(s)
Inhibidores de las Cinasas Janus , Trastornos Mieloproliferativos , Neoplasias , Humanos , Janus Quinasa 2/antagonistas & inhibidores , Inhibidores de las Cinasas Janus/uso terapéutico , Modelos Teóricos , Trastornos Mieloproliferativos/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Genetics has played an important role in risk stratification for plasma cell myeloma patients, providing therapeutic guidance. In this study, we investigated the correlation of bone marrow morphologic features and genetic aberrations, including gene expression profiles, translocations, and gene mutations. For the first time we show that high plasma cell volume, diffuse sheet growth pattern, immature cell morphology, high mitotic index, and increased reticulin fibrosis, significantly correlates with high risk disease determined by MyPRS gene expression profiles. Furthermore, we show the association between MyPRS risk stratification and chromosomal alterations and specific gene mutations. We also demonstrate the combinational effect of TP53 mutation and 17p loss on the histological changes in bone marrow.
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Biomarcadores de Tumor/genética , Médula Ósea/patología , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Mutación , Células Plasmáticas/patología , Transcriptoma , Adulto , Anciano , Anciano de 80 o más Años , Aberraciones Cromosómicas , Cromosomas Humanos Par 17 , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Pronóstico , Proteína p53 Supresora de Tumor/genéticaRESUMEN
The Ten-eleven translocation (TET) enzymes regulate gene expression by promoting DNA demethylation and partnering with chromatin modifiers. TET2, a member of this family, is frequently mutated in hematological disorders. The contributions of TET2 in hematopoiesis have been attributed to its DNA demethylase activity, and the significance of its nonenzymatic functions has remained undefined. To dissect the catalytic and non-catalytic requirements of Tet2, we engineered catalytically inactive Tet2 mutant mice and conducted comparative analyses of Tet2 mutant and Tet2 knockout animals. Tet2 knockout mice exhibited expansion of hematopoietic stem and progenitor cells (HSPCs) and developed myeloid and lymphoid disorders, while Tet2 mutant mice predominantly developed myeloid malignancies reminiscent of human myelodysplastic syndromes. HSPCs from Tet2 knockout mice exhibited distinct gene expression profiles, including downregulation of Gata2. Overexpression of Gata2 in Tet2 knockout bone marrow cells ameliorated disease phenotypes. Our results reveal the non-catalytic roles of TET2 in HSPC homeostasis.
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Biocatálisis , Proteínas de Unión al ADN/metabolismo , Células Madre Hematopoyéticas/metabolismo , Homeostasis , Proteínas Proto-Oncogénicas/metabolismo , Animales , Médula Ósea/metabolismo , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Dioxigenasas , Regulación de la Expresión Génica , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patología , Ratones Noqueados , Mutación/genética , Fenotipo , Proteínas Proto-Oncogénicas/deficiencia , Proteínas Proto-Oncogénicas/genéticaRESUMEN
Activation of tumor suppressors for the treatment of human cancer has been a long sought, yet elusive, strategy. PTEN is a critical tumor suppressive phosphatase that is active in its dimer configuration at the plasma membrane. Polyubiquitination by the ubiquitin E3 ligase WWP1 (WW domain-containing ubiquitin E3 ligase 1) suppressed the dimerization, membrane recruitment, and function of PTEN. Either genetic ablation or pharmacological inhibition of WWP1 triggered PTEN reactivation and unleashed tumor suppressive activity. WWP1 appears to be a direct MYC (MYC proto-oncogene) target gene and was critical for MYC-driven tumorigenesis. We identified indole-3-carbinol, a compound found in cruciferous vegetables, as a natural and potent WWP1 inhibitor. Thus, our findings unravel a potential therapeutic strategy for cancer prevention and treatment through PTEN reactivation.