Events

Title of the seminar:

“Mutational synergy with CREBBP loss in lymphomagenesis identified through forward insertional mutagenesis in a new DLBCL mouse model”

Place : Seminar room TPR5, Campus of Luminy, Friday, 8 September, 2023 @ 11 am.

Research outline

Diffuse large B-cell lymphoma (DLBCL) is the most common form of B-cell non-Hodgkin lymphoma. Despite improvements in the treatments, this disease remains incurable in ~40% of the cases. Although CREBBP loss-of-function mutations are often seen in patients, its precise role in driving the disease and its cooperation with additional mutations have not yet been fully uncovered. We established a new DLBCL mouse model that combines Crebbp loss with a transposon-based insertional mutagenesis system. Mx1Cre-mediated Crebbp excision occurs in the HSPC compartment and combines with B-cell lineage restricted transposition of the GrOnc transposon. This model greatly increases the penetrance of B-cell lymphoma, accelerates disease progression and recapitulates more faithfully features of human lymphoma. We have also generated a comparator cohort of mice that are Crebbp replete (Mx1Cre negative). They develop lymphomas of longer latency and differing histology. Detailed analyses of tissues revealed the presence of an aberrant B220low B cell population expressing germinal centre markers. These malignant cells were transplantable and generated an identical aggressive disease. Sequencing analyses of this population demonstrates GrOnc insertions in several critical genes for B-cell development including Pax5 and Ebf1, as well as in targetable signalling pathways. Future work will involve comparisons with patient data, functional validation and therapeutic studies.

List of Publications

• Turchi L, Sakakini N et al. CELF2 sustains the proliferating/OLIG2+ cell population in glioblastoma by epigenetic epigenetic repression of the SOX3 gene. Oncogene. Submitted.
• Agrawal-Singh S, Bagri J, Sakakini N, Huntly B. A guide to epigenetics in leukaemia stem cell. Molecular Oncology. Under review.
• Juban G*, Sakakini N* et al. Oncogenic GATA1 causes stage-specific megakaryocyte differentiation delay. Haematologica. 2020 Jun 11 :haematol.2019.244541. doi: 10.3324/haematol.2019.244541. Online ahead of print. *co-first authors
• Almairac F, Turchi L, Sakakini N et al. ERK-Mediated Loss of miR-199a-3p and Induction of EGR1 Act as a "Toggle Switch" of GBM Cell Dedifferentiation into NANOG- and OCT4-Positive Cells. Cancer Res. 2020 Aug 15;80(16):3236-3250. doi: 10.1158/0008-5472.CAN-19-0855.
• Sakakini N, Turchi L, Bergon A, Holota H, Rekima S, Lopez F, Paquis P, Almairac F, Fontaine D, Baeza-Kallee N, Van Obberghen-Schilling E, Junier MP, Chneiweiss H, Figarella-Branger D, Burel-VandenbosF, Imbert J, Virolle T. A positive feed-forward loop associating EGR1 and PDGFA promotes proliferationand self-renewal in glioblastoma stem cells. J Biol Chem 2016 May 13;291(20):10684-99
• Bouchet A, Sakakini N, Atifi ME, Le Clec'h C, Bräuer-Krisch E, Rogalev L, Laissue JA, Rihet P, Le Duc G, Pelletier L. Identification of AREG and PLK1 pathway modulation as a potential key of the response of intracranial 9L tumor to microbeam radiation therapy. Int J Cancer. 2015 Jun 1;136(11):2705-1
• Bouchet A, Sakakini N, Atifi M, Moisan A, Deman P, Le Clec’h C, Brauer E, Rihet P, Le Duc G, Pelletier L. Early gene expression analysis in 9L orthotopic tumor-bearing rats irradiated with synchrotron microbeam radiation therapy identifies specific molecular response. PLoS One 2013 Dec 31;8(12):e81874
• Maupetit Méhouas S, Azzi S, Steunou V, Sakakini N, Silve C, Reynes C, Perez de Nanclares G, Chantot S, Barlier A, Linglart A, Netchine I. Simultaneous hyper- and hypomethylation at imprinted loci in a subset of patients with GNAS epimutations underlies a complex and different mechanism of multilocus methylation defect in pseudohypoparathyroidism type 1b. Human mutation 2013 Aug;34(8):1172-80