RESUMEN
T-cell acute lymphoblastic leukemia (T-ALL) results from leukemic transformation of T-cell precursors arrested at specific differentiation stages, including an 'early-cortical' thymic maturation arrest characterized by expression of cytoplasmic TCRß but no surface T-cell receptor (TCR) and frequent ectopic expression of the TLX1/3 NK-like homeotic proteins (NKL). We designed a TCRα VJC PCR to identify clonal TCRα rearrangements in 32% of 127 T-ALLs, including 0/52 immature/TCRγδ lineage cases and 41/75 (55%) TCRαß lineage cases. Amongst the latter, TCRα rearrangements were not identified in 30/54 (56%) of IMß/pre-αß early-cortical T-ALLs, of which the majority (21/30) expressed TLX1/3. We reasoned that the remaining T-ALLs might express other NKL proteins, so compared transcript levels of 46 NKL in T-ALL and normal thymic subpopulations. Ectopic overexpression of 10 NKL genes, of which six are unreported in T-ALL (NKX2-3, BARHL1, BARX2, EMX2, LBX2 and MSX2), was detectable in 17/104 (16%) T-ALLs. Virtually all NKL overexpressing T-ALLs were TCRα unrearranged and ectopic NKL transcript expression strongly repressed Eα activity, suggesting that ectopic NKL expression is the major determinant in early-cortical thymic T-ALL maturation arrest. This immunogenetic T-ALL subtype, defined by TCRß VDJ but no TCRα VJ rearrangement, is associated with a favorable outcome in GRAALL-treated adult T-ALLs.
Asunto(s)
Proteínas de Homeodominio/metabolismo , Leucemia-Linfoma de Células T del Adulto/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Adulto , Diferenciación Celular/fisiología , Línea Celular Tumoral , Femenino , Células HeLa , Humanos , MasculinoRESUMEN
The tumour suppressor gene PTEN is commonly altered in T-cell acute lymphoblastic leukaemia but its prognostic impact is still debated. We screened a cohort of 573 fully characterised adult and paediatric T-cell acute lymphoblastic leukaemia (T-ALL) patients for genomic PTEN abnormalities. PTEN-inactivating mutations and/or deletions were identified in 91 cases (16%), including 18% of paediatric (49/277) and 14% of adult cases (42/296). Thirty-four patients harboured only mutations, 12 cases demonstrated only large deletions and 9 only microdeletions. About 36 patients had combined alterations. Different mechanisms of PTEN inactivation predicted differences in the clinical outcome for both adult and paediatric patients treated according to the GRAALL03/05 and FRALLE2000 protocols. Whereas large deletions predicted lower 5-year overall survival (P=0.0053 in adults, P=0.001 in children) and disease-free survival (P=0.0009 in adults, P=0.0002 in children), mutations were not associated with a worse prognosis. The prognostic impact of PTEN loss is therefore linked to the underlying type of genomic abnormality, both in adult and paediatric T-ALLs, demonstrating that detailed analysis of the type of abnormality type would be useful to refine risk stratification.
Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Variación Genética , Fosfohidrolasa PTEN/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Adolescente , Adulto , Factores de Edad , Alelos , Biomarcadores de Tumor , Niño , Preescolar , Hibridación Genómica Comparativa , Exones , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunofenotipificación , Lactante , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Fosfohidrolasa PTEN/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidad , Pronóstico , Eliminación de Secuencia , Análisis de Supervivencia , Flujo de Trabajo , Adulto JovenAsunto(s)
Vectores Genéticos/genética , Lentivirus/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Linfocitos T/metabolismo , Proteínas del Envoltorio Viral/genética , Animales , Línea Celular Tumoral , Técnicas de Transferencia de Gen , Terapia Genética/métodos , Humanos , Ratones , Transducción Genética/métodosRESUMEN
The thymus is the major site for normal and leukemic T-cell development. The dissection of the molecular determinants of T-cell survival and differentiation is paramount for the manipulation of healthy or transformed T cells in cancer (immuno)therapy. Casein kinase 2 (CK2) is a serine/threonine protein kinase whose anti-apoptotic functions have been described in various hematological and solid tumors. Here we disclose an unanticipated role of CK2 in healthy human thymocytes that is selective to the γδ T-cell lineage. γδ thymocytes display higher (and T-cell receptor inducible) CK2 activity than their αß counterparts, and are strikingly sensitive to death upon CK2 inhibition. Mechanistically, we show that CK2 regulates the pro-survival AKT signaling pathway in γδ thymocytes and, importantly, also in γδ T-cell acute lymphoblastic leukemia (T-ALL) cells. When compared with healthy thymocytes or leukemic αß T cells, γδ T-ALL cells show upregulated CK2 activity, potentiated by CD27 costimulation, and enhanced apoptosis upon CK2 blockade using the chemical inhibitor CX-4945. Critically, this results in inhibition of tumor growth in a xenograft model of human γδ T-ALL. These data identify CK2 as a novel survival determinant of both healthy and leukemic γδ T cells, and may thus greatly impact their therapeutic manipulation.
Asunto(s)
Quinasa de la Caseína II/fisiología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/inmunología , Proteínas Proto-Oncogénicas c-akt/fisiología , Receptores de Antígenos de Linfocitos T gamma-delta/análisis , Transducción de Señal/fisiología , Linfocitos T/fisiología , Timo/inmunología , Animales , Quinasa de la Caseína II/antagonistas & inhibidores , Supervivencia Celular , Humanos , Ratones , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/fisiologíaRESUMEN
PTEN is a protein phosphatase that is crucial to prevent the malignant transformation of T-cells. Although a numerous mechanisms regulate its expression and function, they are often altered in T-cell acute lymphoblastic leukaemias and T-cell lymphomas. As such, PTEN inactivation frequently occurs in these malignancies, where it can be associated with chemotherapy resistance and poor prognosis. Different Pten knockout models recapitulated the development of T-cell leukaemia/lymphoma, demonstrating that PTEN loss is at the center of a complex oncogenic network that sustains and drives tumorigenesis via the activation of multiple signalling pathways. These aspects and their therapeutic implications are discussed in this review.