Belver, L., Yang, A.Y., Albero, R., Herranz, D., Brundu, F.G., Quinn, S.A., Pérez-Durán, P., Álvarez, S., Gianni, F., Rashkovan, M., Gurung, D., Rocha, P.P., Raviram, R., Reglero, C., Cortés, J.R., Cooke, A., Wendorff, A., Cordó, V., Meijerink, J., Rabadán, R., and Ferrando, A.A
Gata3-controlled nucleosome eviction drives Myc enhancer activity in T-cell development and leukemia
Cancer Discov. 2019; 9, 1774-1791. , . Long-range enhancers govern the temporal and spatial control of gene expression; however, the mechanisms that regulate enhancer activity during normal and malignant development remain poorly understood. Here, we demonstrate a role for aberrant chromatin accessibility in the regulation of MYC expression in T-cell lymphoblastic leukemia (T-ALL). Central to this process, the NOTCH1-MYC enhancer (N-Me), a long-range T cell–specific MYC enhancer, shows dynamic changes in chromatin accessibility during T-cell specification and maturation and an aberrant high degree of chromatin accessibility in mouse and human T-ALL cells. Mechanistically, we demonstrate that GATA3-driven nucleosome eviction dynamically modulates N-Me enhancer activity and is strictly required for NOTCH1-induced T-ALL initiation and maintenance. These results directly implicate aberrant regulation of chromatin accessibility at oncogenic enhancers as a mechanism of leukemic transformation.
Més informacióCortés, J.R., Ambesi-Impiombato, A., Couronné, L., Quinn, S.A., Kim, C.S., da Silva Almeida, A.C., West, Z., Belver, L., Sánchez-Martín, M., Scourzic, L., Bhagat, G., Bernard, O.A., Ferrando, A.A., and Palomero, T
RHOA G17V Induces T Follicular Helper Cell Specification and Promotes Lymphomagenesis
Cancer Cell. 2018; 33, 259-273. , . Angioimmunoblastic T cell lymphoma (AITL) is an aggressive tumor derived from malignant transformation of T follicular helper (Tfh) cells. AITL is characterized by loss-of-function mutations in Ten-Eleven Translocation 2 (TET2) epigenetic tumor suppressor and a highly recurrent mutation (p.Gly17Val) in the RHOA small GTPase. Yet, the specific role of RHOA G17V in AITL remains unknown. Expression of Rhoa G17V in CD4+ T cells induces Tfh cell specification; increased proliferation associated with inducible co-stimulator (ICOS) upregulation and increased phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase signaling. Moreover, RHOA G17V expression together with Tet2 loss resulted in development of AITL in mice. Importantly, Tet2-/-RHOA G17V tumor proliferation in vivo can be inhibited by ICOS/PI3K-specific blockade, supporting a driving role for ICOS signaling in Tfh cell transformation.
Més informacióBelver, L., Ferrando, A.A
The genetics and mechanisms of T-cell acute lymphoblastic leukemia
Nat Rev Cancer. 2016; 16, 494-507. , . T cell acute lymphoblastic leukaemia (T-ALL) is an aggressive haematological malignancy derived from early T cell progenitors. In recent years genomic and transcriptomic studies have uncovered major oncogenic and tumour suppressor pathways involved in T-ALL transformation and identified distinct biological groups associated with prognosis. An increased understanding of T-ALL biology has already translated into new prognostic biomarkers and improved animal models of leukaemia and has opened opportunities for the development of targeted therapies for the treatment of this disease. In this Review we examine our current understanding of the molecular mechanisms of T-ALL and recent developments in the translation of these results to the clinic.
Més informacióPuente, X.S., Beà, S., Valdés-Mas, R., Villamor, N., Gutiérrez-Abril, J., Martín-Subero, J.I., Munar, M., Rubio-Pérez, C., Jares, P., Aymerich, M., Baumann, T., Beekman, R., Belver, L., Carrio, A., Castellano, G., Clot, G., Colado, E., Colomer, D., Costa, D., Delgado, J., Enjuanes, A., Estivill, X., Ferrando, A.A., Gelpí, J.L., González, B., González, S., González, M., Gut, M., Hernández-Rivas, J.M., López-Guerra, M., Martín-García, D., Navarro, A., Nicolás, P., Orozco, M., Payer, Á.R., Pinyol, M., Pisano, D.G., Puente, D.A., Queirós, A.C., Quesada, V., Romeo-Casabona, C.M., Royo, C., Royo, R., Rozman, M., Russiñol, N., Salaverría, I., Stamatopoulos, K., Stunnenberg, H.G., Tamborero, D., Terol, M.J., Valencia, A., López-Bigas, N., Torrents, D., Gut, I., López-Guillermo, A., López-Otín, C., and Campo, E
Non-coding recurrent mutations in chronic lymphocytic leukaemia
Nature. 2015; 526, 519-524 , . Chronic lymphocytic leukaemia (CLL) is a frequent disease in which the genetic alterations determining the clinicobiological behaviour are not fully understood. Here we describe a comprehensive evaluation of the genomic landscape of 452 CLL cases and 54 patients with monoclonal B-lymphocytosis, a precursor disorder. We extend the number of CLL driver alterations, including changes in ZNF292, ZMYM3, ARID1A and PTPN11. We also identify novel recurrent mutations in non-coding regions, including the 3' region of NOTCH1, which cause aberrant splicing events, increase NOTCH1 activity and result in a more aggressive disease. In addition, mutations in an enhancer located on chromosome 9p13 result in reduced expression of the B-cell-specific transcription factor PAX5. The accumulative number of driver alterations (0 to ≥4) discriminated between patients with differences in clinical behaviour. This study provides an integrated portrait of the CLL genomic landscape, identifies new recurrent driver mutations of the disease, and suggests clinical interventions that may improve the management of this neoplasia.
Més informacióHerranz, D., Ambesi-Impiombato, A., Sudderth, J., Sánchez-Martín, M, Belver, L., Tosello, V., Xu, L., Wendorff, A.A., Castillo, M., Haydu, J.E., Márquez, J., Matés, J.M., Kung, A.L., Rayport, S., Cordon-Cardo, C., DeBerardinis, R.J., and Ferrando, A.A
Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia
Nat Med. 2015; 21, 1182-1189. , . Activating mutations in NOTCH1 are common in T cell acute lymphoblastic leukemia (T-ALL). Here we identify glutaminolysis as a critical pathway for leukemia cell growth downstream of NOTCH1 and a key determinant of the response to anti-NOTCH1 therapies in vivo. Mechanistically, inhibition of NOTCH1 signaling in T-ALL induces a metabolic shutdown, with prominent inhibition of glutaminolysis and triggers autophagy as a salvage pathway supporting leukemia cell metabolism. Consequently, inhibition of glutaminolysis and inhibition of autophagy strongly and synergistically enhance the antileukemic effects of anti-NOTCH1 therapy in mice harboring T-ALL. Moreover, we demonstrate that Pten loss upregulates glycolysis and consequently rescues leukemic cell metabolism, thereby abrogating the antileukemic effects of NOTCH1 inhibition. Overall, these results identify glutaminolysis as a major node in cancer metabolism controlled by NOTCH1 and as therapeutic target for the treatment of T-ALL.
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