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Adolfo Ferrando

Giulia Fabbri, Antony B Holmes, Mara Viganotti, Claudio Scuoppo, Laura Belver, Daniel Herranz, Xiao-Jie Yan, Yasmine Kieso, Davide Rossi, Gianluca Gaidano, Nicholas Chiorazzi, Adolfo A Ferrando, Riccardo Dalla-Favera
Activating mutations of NOTCH1 (a well-known oncogene in T-cell acute lymphoblastic leukemia) are present in ∼4-13% of chronic lymphocytic leukemia (CLL) cases, where they are associated with disease progression and chemorefractoriness. However, the specific role of NOTCH1 in leukemogenesis remains to be established. Here, we report that the active intracellular portion of NOTCH1 (ICN1) is detectable in ∼50% of peripheral blood CLL cases lacking gene mutations. We identify a "NOTCH1 gene-expression signature" in CLL cells, and show that this signature is significantly enriched in primary CLL cases expressing ICN1, independent of NOTCH1 mutation...
April 4, 2017: Proceedings of the National Academy of Sciences of the United States of America
Marta Sanchez-Martin, Alberto Ambesi-Impiombato, Yue Qin, Daniel Herranz, Mukesh Bansal, Tiziana Girardi, Elisabeth Paietta, Martin S Tallman, Jacob M Rowe, Kim De Keersmaecker, Andrea Califano, Adolfo A Ferrando
The Notch1 gene is a major oncogenic driver and therapeutic target in T-cell acute lymphoblastic leukemia (T-ALL). However, inhibition of NOTCH signaling with γ-secretase inhibitors (GSIs) has shown limited antileukemic activity in clinical trials. Here we performed an expression-based virtual screening to identify highly active antileukemic drugs that synergize with NOTCH1 inhibition in T-ALL. Among these, withaferin A demonstrated the strongest cytotoxic and GSI-synergistic antileukemic effects in vitro and in vivo...
February 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
Marta Sanchez-Martin, Adolfo Ferrando
T-cell acute lymphoblastic leukemia (T-ALL) is a highly proliferative hematologic malignancy that results from the transformation of immature T-cell progenitors. Aberrant cell growth and proliferation in T-ALL lymphoblasts are sustained by activation of strong oncogenic drivers promoting cell anabolism and cell cycle progression. Oncogenic NOTCH signaling, which is activated in more than 65% of T-ALL patients by activating mutations in the NOTCH1 gene, has emerged as a major regulator of leukemia cell growth and metabolism...
March 2, 2017: Blood
Francesco Abate, Ana C da Silva-Almeida, Sakellarios Zairis, Javier Robles-Valero, Lucile Couronne, Hossein Khiabanian, S Aidan Quinn, Mi-Yeon Kim, Maria Antonella Laginestra, Christine Kim, Danilo Fiore, Govind Bhagat, Miguel Angel Piris, Elias Campo, Izidore S Lossos, Olivier A Bernard, Giorgio Inghirami, Stefano Pileri, Xosé R Bustelo, Raul Rabadan, Adolfo A Ferrando, Teresa Palomero
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of non-Hodgkin lymphomas frequently associated with poor prognosis and for which genetic mechanisms of transformation remain incompletely understood. Using RNA sequencing and targeted sequencing, here we identify a recurrent in-frame deletion (VAV1 Δ778-786) generated by a focal deletion-driven alternative splicing mechanism as well as novel VAV1 gene fusions (VAV1-THAP4, VAV1-MYO1F, and VAV1-S100A7) in PTCL. Mechanistically these genetic lesions result in increased activation of VAV1 catalytic-dependent (MAPK, JNK) and non-catalytic-dependent (nuclear factor of activated T cells, NFAT) VAV1 effector pathways...
January 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
Laura Belver, Adolfo Ferrando
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...
July 25, 2016: Nature Reviews. Cancer
Eun-Jung Ann, Mi-Yeon Kim, Ji-Hye Yoon, Ji-Seon Ahn, Eun-Hye Jo, Hye-Jin Lee, Hyun-Woo Lee, Hyeok-Gu Kang, Dong Wook Choi, Kyung-Hee Chun, Ji Shin Lee, Cheol Yong Choi, Adolfo A Ferrando, Keesook Lee, Hee-Sae Park
The receptor Notch1 plays an important role in malignant progression of many cancers, but its regulation is not fully understood. In this study, we report that the kinase HIPK2 is responsible for facilitating the Fbw7-dependent proteasomal degradation of Notch1 by phosphorylating its intracellular domain (Notch1-IC) within the Cdc4 phosphodegron motif. Notch1-IC expression was higher in cancer cells than normal cells. Under genotoxic stress, Notch1-IC was phosphorylated constitutively by HIPK2 and was maintained at a low level through proteasomal degradation...
August 15, 2016: Cancer Research
Clara Soria-Valles, Ana Gutiérrez-Fernández, Fernando G Osorio, Dido Carrero, Adolfo A Ferrando, Enrique Colado, M Soledad Fernández-García, Elena Bonzon-Kulichenko, Jesús Vázquez, Antonio Fueyo, Carlos López-Otín
Matrix metalloproteases (MMPs) regulate innate immunity acting over proinflammatory cytokines, chemokines, and other immune-related proteins. MMP-25 (membrane-type 6-MMP) is a membrane-bound enzyme predominantly expressed in leukocytes whose biological function has remained largely unknown. We have generated Mmp25-deficient mice to elucidate the in vivo function of this protease. These mutant mice are viable and fertile and do not show any spontaneous phenotype. However, Mmp25-null mice exhibit a defective innate immune response characterized by low sensitivity to bacterial LPS, hypergammaglobulinemia, and reduced secretion of proinflammatory molecules...
July 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Maddalena Paganin, Barbara Buldini, Giuseppe Germano, Elena Seganfreddo, Annamaria di Meglio, Elisa Magrin, Francesca Grillo, Martina Pigazzi, Carmelo Rizzari, Giovanni Cazzaniga, Hossein Khiabanian, Teresa Palomero, Raul Rabadan, Adolfo A Ferrando, Giuseppe Basso
A 4-year-old male with the diagnosis of T-cell acute lymphoblastic leukemia (T-ALL) relapsed after 19 months with an acute myeloid leukemia (AML). Immunoglobulin and T-cell receptor gene rearrangements analyses reveal that both leukemias were rearranged with a clonal relationship between them. Comparative genomic hybridization (Array-CGH) and whole-exome sequencing analyses of both samples suggest that this leukemia may have originated from a common T/myeloid progenitor. The presence of homozygous deletion of p16/INK4A, p14/ARF, p15/INK4B, and heterozygous deletion of WT1 locus remained stable in the leukemia throughout phenotypic switch, revealing that this AML can be genetically associated to T-ALL...
September 2016: Pediatric Blood & Cancer
Daniel Herranz, Adolfo A Ferrando
No abstract text is available yet for this article.
2016: Cell Cycle
Ana Carolina da Silva Almeida, Francesco Abate, Hossein Khiabanian, Estela Martinez-Escala, Joan Guitart, Cornelis P Tensen, Maarten H Vermeer, Raul Rabadan, Adolfo Ferrando, Teresa Palomero
Sézary syndrome is a leukemic and aggressive form of cutaneous T cell lymphoma (CTCL) resulting from the malignant transformation of skin-homing central memory CD4(+) T cells. Here we performed whole-exome sequencing of tumor-normal sample pairs from 25 patients with Sézary syndrome and 17 patients with other CTCLs. These analyses identified a distinctive pattern of somatic copy number alterations in Sézary syndrome, including highly prevalent chromosomal deletions involving the TP53, RB1, PTEN, DNMT3A and CDKN1B tumor suppressors...
December 2015: Nature Genetics
Nicole Kucine, Sachie Marubayashi, Neha Bhagwat, Efthymia Papalexi, Priya Koppikar, Marta Sanchez Martin, Lauren Dong, Marty S Tallman, Elisabeth Paietta, Kai Wang, Jie He, Doron Lipson, Phil Stephens, Vince Miller, Jacob M Rowe, Julie Teruya-Feldstein, Charles G Mullighan, Adolfo A Ferrando, Andrei Krivtsov, Scott Armstrong, Laura Leung, Stefan O Ochiana, Gabriela Chiosis, Ross L Levine, Maria Kleppe
The development of the dual Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib for the treatment of myeloproliferative neoplasms (MPNs) has led to studies of ruxolitinib in other clinical contexts, including JAK-mutated acute lymphoblastic leukemia (ALL). However, the limited ability of JAK inhibition to induce molecular or clinicopathological responses in MPNs suggests a need for development of better therapies for JAK kinase-dependent malignancies. Here, we demonstrate that heat shock protein 90 (HSP90) inhibition using a purine-scaffold HSP90 inhibitor in early clinical development is an effective therapeutic approach in JAK-dependent ALL and can overcome persistence to JAK-inhibitor therapy in ALL cells...
November 26, 2015: Blood
Daniel Herranz, Alberto Ambesi-Impiombato, Jessica Sudderth, Marta Sánchez-Martín, Laura Belver, Valeria Tosello, Luyao Xu, Agnieszka A Wendorff, Mireia Castillo, J Erika Haydu, Javier Márquez, José M Matés, Andrew L Kung, Stephen Rayport, Carlos Cordon-Cardo, Ralph J DeBerardinis, Adolfo A Ferrando
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...
October 2015: Nature Medicine
Xose S Puente, Silvia Beà, Rafael Valdés-Mas, Neus Villamor, Jesús Gutiérrez-Abril, José I Martín-Subero, Marta Munar, Carlota Rubio-Pérez, Pedro Jares, Marta Aymerich, Tycho Baumann, Renée Beekman, Laura Belver, Anna Carrio, Giancarlo Castellano, Guillem Clot, Enrique Colado, Dolors Colomer, Dolors Costa, Julio Delgado, Anna Enjuanes, Xavier Estivill, Adolfo A Ferrando, Josep L Gelpí, Blanca González, Santiago González, Marcos González, Marta Gut, Jesús M Hernández-Rivas, Mónica López-Guerra, David Martín-García, Alba Navarro, Pilar Nicolás, Modesto Orozco, Ángel R Payer, Magda Pinyol, David G Pisano, Diana A Puente, Ana C Queirós, Víctor Quesada, Carlos M Romeo-Casabona, Cristina Royo, Romina Royo, María Rozman, Nuria Russiñol, Itziar Salaverría, Kostas Stamatopoulos, Hendrik G Stunnenberg, David Tamborero, María J Terol, Alfonso Valencia, Nuria López-Bigas, David Torrents, Ivo Gut, Armando López-Guillermo, Carlos López-Otín, Elías Campo
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...
October 22, 2015: Nature
Lauren A Pitt, Anastasia N Tikhonova, Hai Hu, Thomas Trimarchi, Bryan King, Yixiao Gong, Marta Sanchez-Martin, Aris Tsirigos, Dan R Littman, Adolfo A Ferrando, Sean J Morrison, David R Fooksman, Iannis Aifantis, Susan R Schwab
The role of the microenvironment in T cell acute lymphoblastic leukemia (T-ALL), or any acute leukemia, is poorly understood. Here we demonstrate that T-ALL cells are in direct, stable contact with CXCL12-producing bone marrow stroma. Cxcl12 deletion from vascular endothelial, but not perivascular, cells impeded tumor growth, suggesting a vascular niche for T-ALL. Moreover, genetic targeting of Cxcr4 in murine T-ALL after disease onset led to rapid, sustained disease remission, and CXCR4 antagonism suppressed human T-ALL in primary xenografts...
June 8, 2015: Cancer Cell
Hyung-Ok Lee, Xiao He, Jayati Mookerjee-Basu, Dai Zhongping, Xiang Hua, Emmanuelle Nicolas, Maria Luisa Sulis, Adolfo A Ferrando, Joseph R Testa, Dietmar J Kappes
The transcription factor T-helper-inducing POZ/Krueppel-like factor (ThPOK, encoded by the Zbtb7b gene) plays widespread and critical roles in T-cell development, particularly as the master regulator of CD4 commitment. Here we show that mice expressing a constitutive T-cell-specific ThPOK transgene (ThPOK(const) mice) develop thymic lymphomas. These tumors resemble human T-cell acute lymphoblastic leukemia (T-ALL), in that they predominantly exhibit activating Notch1 mutations. Lymphomagenesis is prevented if thymocyte development is arrested at the DN3 stage by recombination-activating gene (RAG) deficiency, but restored by introduction of a T-cell receptor (TCR) transgene or by a single injection of anti-αβTCR antibody into ThPOK(const) RAG-deficient mice, which promotes development to the CD4(+)8(+) (DP) stage...
June 23, 2015: Proceedings of the National Academy of Sciences of the United States of America
Mark R Litzow, Adolfo A Ferrando
T-cell immunophenotype of acute lymphoblastic leukemia (T-ALL) is an uncommon aggressive leukemia that can present with leukemic and/or lymphomatous manifestations. Molecular studies are enhancing our understanding of the pathogenesis of T-ALL, and the discovery of activating mutations of NOTCH1 and FBXW7 in a majority of patients has been a seminal observation. The use of pediatric intensive combination chemotherapy regimens in adolescents and young adults has significantly improved the outcome of patients with T-ALL...
August 13, 2015: Blood
Benshang Li, Hui Li, Yun Bai, Renate Kirschner-Schwabe, Jun J Yang, Yao Chen, Gang Lu, Gannie Tzoneva, Xiaotu Ma, Tongmin Wu, Wenjing Li, Haisong Lu, Lixia Ding, Huanhuan Liang, Xiaohang Huang, Minjun Yang, Lei Jin, Hui Kang, Shuting Chen, Alicia Du, Shuhong Shen, Jianping Ding, Hongzhuan Chen, Jing Chen, Arend von Stackelberg, Longjun Gu, Jinghui Zhang, Adolfo Ferrando, Jingyan Tang, Shengyue Wang, Bin-Bing S Zhou
Relapse is the leading cause of mortality in children with acute lymphoblastic leukemia (ALL). Among chemotherapeutics, thiopurines are key drugs in ALL combination therapy. Using whole-exome sequencing, we identified relapse-specific mutations in the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1), which encodes a rate-limiting purine biosynthesis enzyme, in 24/358 (6.7%) relapsed childhood B cell ALL (B-ALL) cases. All individuals who harbored PRPS1 mutations relapsed early during treatment, and mutated ALL clones expanded exponentially before clinical relapse...
June 2015: Nature Medicine
Stephanie A Schnell, Alberto Ambesi-Impiombato, Marta Sanchez-Martin, Laura Belver, Luyao Xu, Yue Qin, Ryoichiro Kageyama, Adolfo A Ferrando
Oncogenic activation of NOTCH1 signaling plays a central role in the pathogenesis of T-cell acute lymphoblastic leukemia, with mutations on this signaling pathway affecting more than 60% of patients at diagnosis. However, the transcriptional regulatory circuitries driving T-cell transformation downstream of NOTCH1 remain incompletely understood. Here we identify Hairy and Enhancer of Split 1 (HES1), a transcriptional repressor controlled by NOTCH1, as a critical mediator of NOTCH1-induced leukemogenesis strictly required for tumor cell survival...
April 30, 2015: Blood
Laura Belver, Adolfo A Ferrando
Kleppe and colleagues use detailed cytokine profiling analyses to investigate the role of aberrant proinflammatory cytokine secretion in the pathogenesis of myeloproliferative neoplasms. Their analyses implicate constitutive activation of STAT3 in both malignant and nonmalignant bone marrow cell populations as a driver of aberrant cytokine secretion and as a cellular target mediating the therapeutic activity of ruxolitinib.
March 2015: Cancer Discovery
Daniel Herranz, Adolfo A Ferrando
No abstract text is available yet for this article.
2015: Cell Cycle
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