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Material complementario: https://www.mdpi.com/article/10.3390/cancers14071676/s1 Clinical and molecular heterogeneity are hallmarks of chronic lymphocytic leukemia (CLL), a neoplasm characterized by accumulation of mature and clonal long-lived CD5 + B-lymphocytes.Mutational status of the IgHV gene of leukemic clones is a powerful prognostic tool in CLL, and it is well established that unmutated CLLs (U-CLLs) have worse evolution than mutated cases. Nevertheless, progression and treatment requirement of patients can evolve independently from the mutational status. Microenvironment signaling or epigenetic changes partially explain this different behavior. Thus, we think that detailed characterization of the miRNAs landscape from patients with different clinical evolution could facilitate the understanding of this heterogeneity. Since miRNAs are key players in leukemia pathogenesis and evolution, we aim to better characterize different CLL behaviors by comparing the miRNome of clinically progressive U-CLLs vs. stable U-CLLs. Our data show up-regulation of miR-26b-5p, miR-106b-5p, and miR-142-5p in progressive cases and indicate a key role for miR-26b-5p during CLL progression. Specifically, up-regulation of miR-26b-5p in CLL cells blocks TGF-B/SMAD pathway by down-modulation of SMAD-4, resulting in lower expression of p21Cip1 kinase inhibitor and higher expression of c-Myc oncogene. This work describes a new molecular mechanism linking CLL progression with TGF-B modulation and proposes an alternative strategy to explore in CLL therapy. ANII: FSGSK_ 1_2017_1_146663

Activation-induced cytidine deaminase (AID) initiates somatic hypermutation and class switch recombination of the immunoglobulin genes. As a trade-off for its physiological function, AID also contributes to tumor development through its mutagenic activity. In chronic lymphocytic leukemia (CLL), AID is overexpressed in the proliferative fractions (PFs) of the malignant B lymphocytes, and its anomalous expression has been associated with a clinical poor outcome. Recent preclinical data suggested that ibrutinib and idelalisib, 2 clinically approved kinase inhibitors, increase AID expression and genomic instability in normal and neoplastic B cells. These results raise concerns about a potential mutagenic risk in patients receiving long-term therapy. To corroborate these findings in the clinical setting, we analyzed AID expression and PFs in a CLL cohort before and during ibrutinib treatment. We found that ibrutinib decreases the CLL PFs and, interestingly, also reduces AID expression, which correlates with dampened AKT and Janus Kinase 1 signaling. Moreover, although ibrutinib increases AID expression in a CLL cell line, it is unable to do so in primary CLL samples. Our results uncover a differential response to ibrutinib between cell lines and the CLL clone and imply that ibrutinib could differ from idelalisib in their potential to induce AID in treated patients. Possible reasons for the discrepancy between preclinical and clinical findings, and their effect on treatment safety, are discussed. Fil: Morande, Pablo Elías. Instituto Pasteur de Montevideo; Uruguay. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Sivina, Mariela. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos Fil: Uriepero, Angimar. Instituto Pasteur de Montevideo; Uruguay Fil: Seija, Noé. Instituto Pasteur de Montevideo; Uruguay Fil: Berca, Catalina. Instituto Pasteur de Montevideo; Uruguay Fil: Fresia, Pablo. Instituto Pasteur de Montevideo; Uruguay Fil: Landoni, Ana Inés. Ministerio de Salud.Hospital Maciel. Administración de los Servicios de Salud del Estado; Uruguay Fil: Di Noia, Javier M.. University of Montreal; Canadá. Cliniques de Montreal. Institut de Recherches. Division of Immunity and Viral Infections; Canadá Fil: Burger, Jan A.. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos Fil: Oppezzo, Pablo. Instituto Pasteur de Montevideo; Uruguay