Authors: M. Quijada‐Álamo, M. Hernández‐Sánchez, A.E. Rodríguez‐Vicente, M. Martín‐Izquierdo, J.M. Hernández‐Sánchez, J.M. Bastida, T. González, V. Alonso‐Pérez, I. García‐Tuñón, J. Galende, C. Aguilar, J.A. Queizán, M.J. Vidal‐Manceñido, R. Benito, J.L. Ordóñez, C.J. Wu, J.M. Hernández‐Rivas
Published: 2019-06-17
DOI: 10.1097/01.hs9.0000561864.73186.e8
Source: Full article
Background:Loss of the long arm of chromosome 11, del(11q), is one of the most common alterations in CLL. ATM gene is mutated in the remaining allele in one third of del(11q) CLL patients, resulting in a complete loss‐of‐function of ATM protein, which is related with poor clinical outcomes. Although targeted BCR inhibition has made a paradigm shift in CLL therapy, relapsed/refractory del(11q) CLLs still show inferior responses to ibrutinib and some patients have developed resistances to these inhibitors overtime. Therefore, novel therapeutic approaches need to be explored in this high‐risk subgroup of patients.Aims:To assess the antiproliferative effects of the combination of PARP inhibiton (olaparib) and BCR inhibition (ibrutinib) in CRISPR/Cas9‐engineeered del(11q)/ATM‐mutated CLL cell lines as well as in primary CLL cells with del(11q) in the presence of the stromal microenvironment.Methods:The CRISPR/Cas9 system was used to introduce del(11q) and ATM mutations (ATM