Differential inhibition of LINE1 and LINE2 retrotransposition by vertebrate AID/APOBEC proteins

BACKGROUND: The role of AID/APOBEC proteins in the mammalian immune response against retroviruses and retrotransposons is well established. G to A hypermutations, the hallmark of their cytidine deaminase activity, are present in several mammalian retrotransposons. However, the role of AID/APOBEC proteins in non-mammalian retroelement restriction is not completely understood. RESULTS: Here we provide the first evidence of anti-retroelement activity of a reptilian APOBEC protein. The green anole lizard A1 protein displayed potent DNA mutator activity and inhibited ex vivo retrotransposition of LINE1 and LINE2 ORF1 protein encoding elements, displaying a mechanism of action similar to that of the human A1 protein. In contrast, the human A3 proteins did not require ORF1 protein to inhibit LINE retrotransposition, suggesting a differential mechanism of anti-LINE action of A1 proteins, which emerged in amniotes, and A3 proteins, exclusive to placental mammals. In accordance, genomic analyses demonstrate differential G to A DNA editing of LINE retrotransposons in the lizard genome, which is also the first evidence for G to A DNA editing in non-mammalian genomes. CONCLUSION: Our data suggest that vertebrate APOBEC proteins differentially inhibit the retrotransposition of LINE elements and that the anti-retroelement activity of APOBEC proteins predates mammals

IGLV3-21R110 mutation has prognostic value in patients with treatment-naive chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) has high biological and clinical heterogeneity.1,2 A few prognostic factors are used in clinical practice, including immunoglobulin heavy-chain variable (IGHV) gene somatic hypermutation (SHM) status, chromosome aberrations, and gene mutations, which remain insufficient for personalized patient management.3,4 Recent studies have shown that expression of the immunoglobulin lambda light chain IGLV3-21 gene carrying an SHM-derived G>C mutation changing the glycine at position 110 to an arginine (IGLV3-21R110) defines a subset of CLL with an intermediate epigenetic profile and an aggressive clinical course.5,6 When occurring on the IGLV3-21∗01 or ∗04 alleles, the R110 mutation allows homotypic B-cell receptor (BCR) interactions, triggering cell-autonomous BCR signaling5,7 and/or facilitating T-cell–independent engagement with superantigen.8 IGLV3-21R110 has been detected in up to 6.5% of patients with CLL at diagnosis and in up to 25% of patients enrolled in clinical trials.5,6,9 We6 and others5 have shown that all CLL cases belonging to aggressive stereotyped subset #2 carried the IGLV3-21R110. Nonetheless, approximately half of IGLV3-21R110 CLL are not classified as stereotyped subset #2 but seem to have a similar clinical outcome,5,6 suggesting that the conventional stereotyped subset #2 classification might not completely recognize this clinically aggressive subgroup of CLL. In addition, IGLV3-21R110 seems to have a prognostic value independent of the IGHV gene SHM status and methylation–based epigenetic subtypes.5,6 However, further studies in independent cohorts are needed to support its application in clinical practice.1,2,10-12 The aim of this study was to assess the prognostic value of IGLV3-21R110 in large and independent population-based cohorts of patients with CLL.This study was supported by the “la Caixa” Foundation (CLLEvolution - LCF/PR/HR17/52150017 [HR17-00221LCF] and CLLSYSTEMS - LCF/PR/HR22/52420015 [HR22-00172] Health Research 2017 and 2022 Programs; E. Colado), the Ministry of Science and Innovation (MCIN/AEI/10.13039/501100011033) and the European Regional Development Fund “Una manera de hacer Europa” (PID2021-123054OB-I00; E. Campo), European Union (EU) NextGenerationEU/Mecanismo para la Recuperación y la Resiliencia and the Instituto de Salud Carlos III (PMP15/00007; E. Campo), the European Research Council under the EU’s Horizon 2020 Research and Innovation Program (810287, BCLLatlas; E. Campo and J.I.M.-S.), the Generalitat de Catalunya Suport Grups de Recerca AGAUR (2017-SGR-1142 and 2021-SGR-01172; E. Campo), the National Institutes of Health/National Cancer Institute grant P01 CA206978 (C.J.W. and G.G.), and the Centro de Investigación Biomédica en Red de Cáncer. H.P.-A. is a recipient of a predoctoral fellowship from the Spanish Ministry of Universities (FPU19/03110). M.D.-F. acknowledges research support from the Asociación Española Contra el Cáncer Scientific Foundation. B.A.K. was supported by a long-term European Molecular Biology Organization fellowship (ALTF 14-2018). C.K.H. was supported by the National Heart, Lung, and Blood Institute Training Program in Molecular Hematology (T32HL116324). F.N. acknowledges research support from the American Association for Cancer Research (2021 AACR-Amgen Fellowship in Clinical/Translational Cancer Research, 21-40-11-NADE), European Hematology Association (EHA Junior Research grant 2021, RG-202012-00245), and Lady Tata Memorial Trust (International Award for Research in Leukaemia 2021-2022, LADY_TATA_21_3223). E. Campo is an academia researcher of the “Institució Catalana de Recerca I Estudis Avançats” of the Generalitat de Catalunya. This work was partially developed at the Centre Esther Koplowitz (Barcelona, Spain).Peer reviewe

Elevated RNA Editing Activity Is a Major Contributor to Transcriptomic Diversity in Tumors

Genomic mutations in key genes are known to drive tumorigenesis and have been the focus of much attention in recent years. However, genetic content also may change farther downstream. RNA editing alters the mRNA sequence from its genomic blueprint in a dynamic and flexible way. A few isolated cases of editing alterations in cancer have been reported previously. Here, we provide a transcriptome-wide characterization of RNA editing across hundreds of cancer samples from multiple cancer tissues, and we show that A-to-I editing and the enzymes mediating this modification are significantly altered, usually elevated, in most cancer types. Increased editing activity is found to be associated with patient survival. As is the case with somatic mutations in DNA, most of these newly introduced RNA mutations are likely passengers, but a few may serve as drivers that may be novel candidates for therapeutic and diagnostic purposes

Multifunctional barcoding with ClonMapper enables high-resolution study of clonal dynamics during tumor evolution and treatment

Lineage-tracing methods have enabled characterization of clonal dynamics in complex populations, but generally lack the ability to integrate genomic, epigenomic and transcriptomic measurements with live-cell manipulation of specific clones of interest. We developed a functionalized lineage-tracing system, ClonMapper, which integrates DNA barcoding with single-cell RNA sequencing and clonal isolation to comprehensively characterize thousands of clones within heterogeneous populations. Using ClonMapper, we identified subpopulations of a chronic lymphocytic leukemia cell line with distinct clonal compositions, transcriptional signatures and chemotherapy survivorship trajectories; patterns that were also observed in primary human chronic lymphocytic leukemia. The ability to retrieve specific clones before, during and after treatment enabled direct measurements of clonal diversification and durable subpopulation transcriptional signatures. ClonMapper is a powerful multifunctional approach to dissect the complex clonal dynamics of tumor progression and therapeutic response