000150965 001__ 150965
000150965 005__ 20251017144605.0
000150965 0247_ $$2doi$$a10.1002/ctm2.304
000150965 0248_ $$2sideral$$a124031
000150965 037__ $$aART-2021-124031
000150965 041__ $$aeng
000150965 100__ $$aQuijada-Alamo, M.
000150965 245__ $$aDissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia
000150965 260__ $$c2021
000150965 5060_ $$aAccess copy available to the general public$$fUnrestricted
000150965 5203_ $$aBackground Several genetic alterations have been identified as driver events in chronic lymphocytic leukemia (CLL) pathogenesis and oncogenic evolution. Concurrent driver alterations usually coexist within the same tumoral clone, but how the cooperation of multiple genomic abnormalities contributes to disease progression remains poorly understood. Specifically, the biological and clinical consequences of concurrent high-risk alterations such as del(11q)/ATM-mutations and del(17p)/TP53-mutations have not been established. Methods We integrated next-generation sequencing (NGS) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 techniques to characterize the in vitro and in vivo effects of concurrent monoallelic or biallelic ATM and/or TP53 alterations in CLL prognosis, clonal evolution, and therapy response. Results Targeted sequencing analysis of the co-occurrence of high-risk alterations in 271 CLLs revealed that biallelic inactivation of both ATM and TP53 was mutually exclusive, whereas monoallelic del(11q) and TP53 alterations significantly co-occurred in a subset of CLL patients with a highly adverse clinical outcome. We determined the biological effects of combined del(11q), ATM and/or TP53 mutations in CRISPR/Cas9-edited CLL cell lines. Our results showed that the combination of monoallelic del(11q) and TP53 mutations in CLL cells led to a clonal advantage in vitro and in in vivo clonal competition experiments, whereas CLL cells harboring biallelic ATM and TP53 loss failed to compete in in vivo xenotransplants. Furthermore, we demonstrated that CLL cell lines harboring del(11q) and TP53 mutations show only partial responses to B cell receptor signaling inhibitors, but may potentially benefit from ATR inhibition. Conclusions Our work highlights that combined monoallelic del(11q) and TP53 alterations coordinately contribute to clonal advantage and shorter overall survival in CLL.
000150965 536__ $$9info:eu-repo/grantAgreement/ES/ISCIII/PI15-01471$$9info:eu-repo/grantAgreement/ES/ISCIII/PI18-01500$$9info:eu-repo/grantAgreement/ES/MINECO/RD12-0036-0069
000150965 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttps://creativecommons.org/licenses/by/4.0/deed.es
000150965 590__ $$a8.554$$b2021
000150965 591__ $$aONCOLOGY$$b41 / 245 = 0.167$$c2021$$dQ1$$eT1
000150965 591__ $$aMEDICINE, RESEARCH & EXPERIMENTAL$$b24 / 139 = 0.173$$c2021$$dQ1$$eT1
000150965 592__ $$a0.13$$b2021
000150965 593__ $$aMolecular Medicine$$c2021$$dQ4
000150965 593__ $$aMedicine (miscellaneous)$$c2021$$dQ4
000150965 594__ $$a1.3$$b2021
000150965 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000150965 700__ $$aPerez-Carretero, C.
000150965 700__ $$aHernandez-Sanchez, M.
000150965 700__ $$aRodriguez-Vicente, A.E.
000150965 700__ $$aHerrero, A.B.
000150965 700__ $$aHernandez-Sanchez, J.M.
000150965 700__ $$aMartin-Izquierdo, M.
000150965 700__ $$aSantos-Minguez, S.
000150965 700__ $$aDel Rey, M.
000150965 700__ $$aGonzalez, T.
000150965 700__ $$aRubio-Martinez, A.$$uUniversidad de Zaragoza
000150965 700__ $$ade Coca, A.G.
000150965 700__ $$aDavila-Valls, J.
000150965 700__ $$aHernandez-Rivas, J.A.
000150965 700__ $$aParker, H.
000150965 700__ $$aStrefford, J.C.
000150965 700__ $$aBenito, R.
000150965 700__ $$aOrdonez, J.L.
000150965 700__ $$aHernandez-Rivas, J.M.
000150965 7102_ $$11007$$2183$$aUniversidad de Zaragoza$$bDpto. Medicina, Psiqu. y Derm.$$cÁrea Dermatología
000150965 773__ $$g11, 2 (2021), e304 [19 pp.]$$tClinical and Translational Medicine$$x2001-1326
000150965 8564_ $$s3820266$$uhttps://zaguan.unizar.es/record/150965/files/texto_completo.pdf$$yVersión publicada
000150965 8564_ $$s2237812$$uhttps://zaguan.unizar.es/record/150965/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000150965 909CO $$ooai:zaguan.unizar.es:150965$$particulos$$pdriver
000150965 951__ $$a2025-10-17-14:15:13
000150965 980__ $$aARTICLE