RESUMEN
ABSTRACT: Multiple myeloma (MM) cells are addicted to MYC and its direct transactivation targets IRF4 for proliferation and survival. MYC and IRF4 are still considered "undruggable," as most small-molecule inhibitors suffer from low potency, suboptimal pharmacokinetic properties, and undesirable off-target effects. Indirect inhibition of MYC/IRF4 emerges as a therapeutic vulnerability in MM. Here, we uncovered an unappreciated tumor-suppressive role of C-terminal binding protein 2 (CTBP2) in MM via strong inhibition of the MYC-IRF4 axis. In contrast to epithelial cancers, CTBP2 is frequently downregulated in MM, in association with shortened survival, hyperproliferative features, and adverse clinical outcomes. Restoration of CTBP2 exhibited potent antitumor effects against MM in vitro and in vivo, with marked repression of the MYC-IRF4 network genes. Mechanistically, CTBP2 impeded the transcription of MYC and IRF4 by histone H3 lysine 27 deacetylation (H3K27ac) and indirectly via activation of the MYC repressor IFIT3. In addition, activation of the interferon gene signature by CTBP2 suggested its concomitant immunomodulatory role in MM. Epigenetic studies have revealed the contribution of polycomb-mediated silencing and DNA methylation to CTBP2 inactivation in MM. Notably, inhibitors of Enhance of zeste homolog 2, histone deacetylase, and DNA methyltransferase, currently under evaluation in clinical trials, were effective in restoring CTBP2 expression in MM. Our findings indicated that the loss of CTBP2 plays an essential role in myelomagenesis and deciphers an additional mechanistic link to MYC-IRF4 dysregulation in MM. We envision that the identification of novel critical regulators will facilitate the development of selective and effective approaches for treating this MYC/IRF4-addicted malignancy.
Asunto(s)
Oxidorreductasas de Alcohol , Proteínas Co-Represoras , Factores Reguladores del Interferón , Mieloma Múltiple , Proteínas Proto-Oncogénicas c-myc , Animales , Humanos , Ratones , Oxidorreductasas de Alcohol/metabolismo , Oxidorreductasas de Alcohol/antagonistas & inhibidores , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Factores Reguladores del Interferón/metabolismo , Factores Reguladores del Interferón/genética , Mieloma Múltiple/metabolismo , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas Supresoras de Tumor/metabolismo , Proteínas Co-Represoras/antagonistas & inhibidores , Proteínas Co-Represoras/metabolismoRESUMEN
We describe a case of coexisting BCR-ABL negative myeloproliferative disorder and precursor T-cell lymphoblastic lymphoma associated with t(8;13) involving FGFR1 at 8p11 in a 14-year-old boy who presented with generalized lymphadenopathy and an abdominal mass. JAK2 mutation and FIP1L1-PDGFRalpha were not detected. RT-PCR revealed the ZNF198-FGFR1 fusion transcript in both the bone marrow (BM) and lymph node (LN) of the patient at diagnosis. Of interest, reciprocal FGFR1-ZNF198 fusion transcript was demonstrated in the BM but not LN. Also differential clonal TcRgamma gene rearrangements in the BM and LN samples were observed. These findings provide novel insights into the genetic pathogenesis.
Asunto(s)
Cromosomas Humanos Par 13/genética , Cromosomas Humanos Par 8/genética , Trastornos Mieloproliferativos/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Médula Ósea/patología , Transformación Celular Neoplásica/genética , China/epidemiología , Células Clonales , Progresión de la Enfermedad , Genes Codificadores de la Cadena gamma de los Receptores de Linfocito T/genética , Células Madre Hematopoyéticas/patología , Humanos , Masculino , Trastornos Mieloproliferativos/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Inducción de Remisión , Síndrome , Translocación Genética/genéticaRESUMEN
Multiple myeloma is a heterogeneous disease. Its chromosomal abnormalities have been extensively studied with a view to accurate prognostication and personalized therapy. Here, we describe the techniques commonly employed for elucidating chromosomal aberrations, prognostic impact of recurrent chromosomal abnormalities, and recently updated risk stratification systems.
Asunto(s)
Aberraciones Cromosómicas , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/genética , Reordenamiento Génico de Cadena Pesada de Linfocito B , Estudios de Asociación Genética , Sitios Genéticos , Predisposición Genética a la Enfermedad , Humanos , Hibridación Fluorescente in Situ , Interfase/genética , Terapia Molecular Dirigida , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Estadificación de Neoplasias , Poliploidía , Pronóstico , Riesgo , Translocación GenéticaRESUMEN
Cytogenetic investigation of multiple myeloma (MM) has been difficult by conventional methods and most of the data have been derived from western population where incidence of MM is much higher as compared to that of Asians. The current study represents the first report of chromosomal aberrations of multiple myeloma in Chinese. We investigated 25 consecutive Chinese patients with MM for chromosomal aberrations at diagnosis using G-banding and multicolor spectral karyotyping (SKY). Of the 21 patients successfully analyzed by G-banding, 11 patients revealed cytogenetic abnormalities showing complex numerical and structural aberrations, which were further characterized with SKY. An abnormal karyotype significantly associated with blastic MM was observed. Consistent with the western literature, structural rearrangements involving chromosomes 1, 6, 8, 19, numerical abnormalities of gains in chromosomes 9, 3, and 5, and losses in chromosomes 13 and 14 were observed. However, there were notably higher incidences of -22/22q- (4/11) and structural aberrations of chromosome X but a lower incidence of -X. The biological implications of these findings, if confirmed, deserve further evaluation.
Asunto(s)
Aberraciones Cromosómicas , Bandeo Cromosómico/métodos , Cromosomas Humanos/genética , Cariotipificación/métodos , Mieloma Múltiple/genética , Adulto , Anciano , China , Pintura Cromosómica/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/patologíaAsunto(s)
Nefritis Intersticial/diagnóstico , Uveítis/diagnóstico , Lesión Renal Aguda/etiología , Adulto , Anorexia/diagnóstico , Médula Ósea/patología , Fiebre/etiología , Glucocorticoides/uso terapéutico , Humanos , Riñón/patología , Masculino , Nefritis Intersticial/tratamiento farmacológico , Nefritis Intersticial/patología , Recurrencia , SíndromeAsunto(s)
Anemia Sideroblástica/genética , Mutación del Sistema de Lectura , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Proteínas de Transporte de Membrana Mitocondrial/genética , Anemia Sideroblástica/sangre , Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/terapia , Biomarcadores/sangre , Transfusión Sanguínea , Examen de la Médula Ósea , Análisis Mutacional de ADN , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/sangre , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/terapia , Predisposición Genética a la Enfermedad , Humanos , Lactante , FenotipoRESUMEN
UNLABELLED: Neutropenia, secondary to immune destruction or maturation arrest, is the most commonly described adverse haematological effect of beta-lactam antibiotics. We describe a case of reversible pancytopenia, with evidence of hypocellular marrow, after a prolonged course of piperacillin/tazobactam for 26 days. KEYWORDS: Piperacillin; Tazobactam; Myelosuppression; Neutropenia.