Examinando por Autor "Malumbres, Raquel"

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A cyclin-D1 interaction with BAX underlies its oncogenic role and potential as a therapeutic target in mantle cell lymphoma
(National Academy of Sciences of the United States of America, 2011-07-11) Beltran, Elena; Fresquet, Vicente; Martinez-Useros, Javier; Richter-Larrea, Jose A.; Sagardoy, Ainara; Sesma, Izaskun; Almada, Luciana L.; Montes-Serrano, Santiago; Siebert, Reiner; Gesk, Stefan; Calasanz, María J.; Malumbres, Raquel; Rieger, Melissa; Prosper, Felipe; Lossos, Izidore S.; Piris, Miguel Angel; Fernandez-Zapico, Martin E.; Martinez-Climent, Jose A.
The chromosomal translocationt(11;14)(q13;q32) leading to cyclin-D1 overexpression plays an essential role in the development ofmantle cell lymphoma (MCL), an aggressive tumor that remains in-curable with current treatment strategies. Cyclin-D1 has been pos-tulated as an effective therapeutic target, but the evaluation of thistarget has been hampered by our incomplete understanding of itsoncogenic functions and by the lack of valid MCL murine models. Toaddress these issues, we generated a cyclin-D1–driven mouse modelin which cyclin-D1 expression can be regulated externally. Thesemice developed cyclin-D1–expressing lymphomas capable of recapit-ulating features of human MCL. We found that cyclin-D1 inactiva-tion was not sufficient to induce lymphoma regression in vivo;however, using a combination of in vitro and in vivo assays, weidentified a novel prosurvival cyclin-D1 function in MCL cells. Specif-ically, we found that cyclin-D1, besides increasing cell proliferationthrough deregulation of the cell cycle at the G1–S transition, seques-trates the proapoptotic protein BAX in the cytoplasm, thereby fa-voring BCL2’s antiapoptotic function. Accordingly, cyclin-D1 inhi-bition sensitized the lymphoma cells to apoptosis through BAXrelease. Thus, genetic or pharmacologic targeting of cyclin-D1 com-bined with a proapoptotic BH3 mimetic synergistically killed thecyclin-D1–expressing murine lymphomas, human MCL cell lines,and primary lymphoma cells. Our study identifies a role of cyclin-D1 in deregulating apoptosis in MCL cells, and highlights the poten-tial benefit of simultaneously targeting cyclin-D1 and survival path-ways in patients with MCL. This effective combination therapy alsomight be exploited in other cyclin-D1–expressing tumors.
High-throughput sequencing analysis of the chromosome 7q32 deletion reveals IRF5 as a potential tumour suppressor in splenic marginal-zone lymphoma
(Blackwell Publishing, 2012-07-23) Fresquet, Vicente; Robles, Eloy F.; Parker, Anton; Martinez-Useros, Javier; Mena, Maria; Malumbres, Raquel; Agirre, Xabier; Catarino, Susana; Arteta, David; Osaba, Lourdes; Mollejo, Manuela; Hernandez-Rivas, Jesus M.; Calasanz, María José; Daibata, Masanori; Dyer, Martin J. S.; Prosper, Felipe; Vizcarra, Esperanza; Piris, Miguel A.; Oscier, David; Martinez-Climent, Jose A.
Using high-resolution genomic microarray analysis, a distinct genomic pro-file was defined in 114 samples from patients with splenic marginal zonelymphoma (SMZL). Deletion or uniparental disomy of chromosome 7qwere detected in 42 of 114 (37%) SMZLs but in only nine of 170 (5%)mature B-cell lymphomas (P<0 00001). The presence of unmutatedIGHV, genomic complexity, 17p13-TP53deletion and 8q-MYCgain, butnot 7q deletion, correlated with shorter overall survival of SMZL patients.Mapping studies narrowed down a commonly deleted region of 2 7Mbin7q32.1-q32.2 spanning a region between theSND1andCOPG2genes.High-throughput sequencing analysis of the 7q32-deleted segment did notidentify biallelic deletions/insertions or clear pathogenic gene mutations,but detected six nucleotide changes inIRF5(n=2),TMEM209(n=2),CALU(n=1) andZC3HC1(n=1) not found in healthy individuals.Comparative expression analysis found a fourfold down-regulation ofIRF5gene in lymphomas with 7q32 deletionversusnon-deleted tumours(P=0 032). Ectopic expression of IRF5 in marginal-zone lymphoma cellsdecreased proliferation and increased apoptosisin vitro, and impaired lym-phoma developmentin vivo. These results show that cryptic deletions,insertions and/or point mutations inactivating genes within 7q32 are notcommon in SMZL, and suggest that IRF5 may be a haploinsufficienttumour suppressor in this lymphoma entity.