Research Papers - School of Education

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Author: search.filters.author.Enver, T

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    PublicationOpen Access
    Author Correction: Aberrant chromatin landscape following loss of the H3. 3 chaperone Daxx in haematopoietic precursors leads to Pu. 1-mediated neutrophilia and inflammation
    (Nature Publishing Group, 2022-01-04) Gerber, J. P; Russ, J; Chandrasekar, V; Offermann, N; Lee, H. M; Spear, S; Guzzi, N; Maida, S; Pattabiraman, S; Zhang, R; Kayvanjoo, A. H; Datta, P; Kasturiarachchi, J. C; Sposito, T; Izotova, N; Händler, K; Adams, P. D; Marafioti, T; Enver, T; Wenzel, J; Beyer, M; Mass, E; Bellodi, C; Schultze, J. L; Capasso, M; Nimmo, R; Salomoni, P
    In the version of this article initially published, there were omissions in the Acknowledgements section. The section has been amended to now include thanks to Daniele Bano, Miriam Stork and other members of their team (DZNE). We also thank Steven Zvi Josefowicz (Cornell University), Hugues de The (College De France/INSERM) and Nada Jabado (McGill University) for input and discussion, Bart Vanhaesebroeck (UCL) for providing the Rosa26CreERT2 mice, the P.S. lab (in particular, Xin Yan, Christina Georgopoulou Manon Chevallot-Beroux and D.A.) for assistance with experiments and scientific discussion, the DZNE Core Facilities, DZNE animal facility, PRECISE, the LIMES animal facility, UCL Core Services and UCL Biological Services.
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    PublicationOpen Access
    Mir142 loss unlocks IDH2 R140-dependent leukemogenesis through antagonistic regulation of HOX genes
    (Nature Publishing Group, 2020-11-10) Marshall, A; Kasturiarachchi, J. C; Datta, P; Guo, Y; Deltcheva, E; James, C; Brown, J; May, G; Anandagoda, N; Jackson, I; Howard, J. K; Ghazaly, E; Brooks, S; Khwaja, A; Araki, M; Araki, K; Linch, D; Lord, G. M; Enver, T; Nimmo, R
    AML is a genetically heterogeneous disease and understanding how diferent co-occurring mutations cooperate to drive leukemogenesis will be crucial for improving diagnostic and therapeutic options for patients. MIR142 mutations have been recurrently detected in IDH-mutated AML samples. Here, we have used a mouse model to investigate the interaction between these two mutations and demonstrate a striking synergy between Mir142 loss-of-function and IDH2R140Q, with only recipients of double mutant cells succumbing to leukemia. Transcriptomic analysis of the non-leukemic single and leukemic double mutant progenitors, isolated from these mice, suggested a novel mechanism of cooperation whereby Mir142 loss-of-function counteracts aberrant silencing of Hoxa cluster genes by IDH2R140Q. Our analysis suggests that IDH2R140Q is an incoherent oncogene, with both positive and negative impacts on leukemogenesis, which requires the action of cooperating mutations to alleviate repression of Hoxa genes in order to advance to leukemia. This model, therefore, provides a compelling rationale for understanding how diferent mutations cooperate to drive leukemogenesis and the context-dependent efects of oncogenic mutations.
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    PublicationOpen Access
    Aberrant chromatin landscape following loss of the H3. 3 chaperone Daxx in haematopoietic precursors leads to Pu. 1-mediated neutrophilia and inflammation
    (Nature Publishing Group, 2021-12) Gerber, J. P; Russ, J; Chandrasekar, V; Offermann, N; Lee, H. M; Spear, S; Guzzi, N; Maida, S; Pattabiraman, S; Zhang, R; Kayvanjoo, A. H; Datta, P; Kasturiarachchi, J. C; Sposito, T; Izotova, N; Händler, K; Adams, P. T; Marafioti, T; Enver, T; Wenzel, J; Beyer, M; Mass, E; Bellodi, C; Schultze, J. L; Capasso, M; Nimmo, R; Salomoni, P
    Defective silencing of retrotransposable elements has been linked to inflammageing, cancer and autoimmune diseases. However, the underlying mechanisms are only partially understood. Here we implicate the histone H3.3 chaperone Daxx, a retrotransposable element repressor inactivated in myeloid leukaemia and other neoplasms, in protection from inflammatory disease. Loss of Daxx alters the chromatin landscape, H3.3 distribution and histone marks of haematopoietic progenitors, leading to engagement of a Pu.1-dependent transcriptional programme for myelopoiesis at the expense of B-cell differentiation. This causes neutrophilia and inflammation, predisposing mice to develop an autoinflammatory skin disease. While these molecular and phenotypic perturbations are in part reverted in animals lacking both Pu.1 and Daxx, haematopoietic progenitors in these mice show unique chromatin and transcriptome alterations, suggesting an interaction between these two pathways. Overall, our findings implicate retrotransposable element silencing in haematopoiesis and suggest a cross-talk between the H3.3 loading machinery and the pioneer transcription factor Pu.1.
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    PublicationOpen Access
    MicroRNA-142 critically regulates group 2 innate lymphoid cell homeostasis and function
    (American Association of Immunologists, 2021-06-01) Kasturiarachchi, J. C; Roberts, L. B; Jowett, G. M; Read, E; Zabinski, T; Berkachy, R; Selkirk, M. E; Jackson, I; Niazi, U; Anandagoda, N; Araki, M; Araki, K; James, C; Enver, T; Nimmo, R; Reis, R; Howard, J. K; Neves, J. F; Lord, G. M
    Innate lymphoid cells are central to the regulation of immunity at mucosal barrier sites, with group 2 innate lymphoid cells (ILC2s) being particularly important in type 2 immunity. In this study, we demonstrate that microRNA(miR)-142 plays a critical, cell-intrinsic role in the homeostasis and function of ILC2s. Mice deficient for miR-142 expression demonstrate an ILC2 progenitor biased development in the bone marrow, and along with peripheral ILC2s at mucosal sites, these cells display a greatly altered phenotype based on surface marker expression. ILC2 proliferative and effector functions are severely dysfunctional following Nippostrongylus brasiliensis infection, revealing a critical role for miR-142 isoforms in ILC2-mediated immune responses. Mechanistically, Socs1 and Gfi1 expression are regulated by miR-142 isoforms in ILC2s, impacting ILC2 phenotypes as well as the proliferative and effector capacity of these cells. The identification of these novel pathways opens potential new avenues to modulate ILC2-dependent immune functions