L2IB studies how lymphoid and myeloid malignancies arise, how they interact with the immune system and their microenvironment, and how that biology can be turned into better diagnosis and treatment. Our work spans epigenetics, genomics, environmental exposure, inflammation and cell therapy, with a transversal computational programme supporting every axis.
Axis 1 — Epigenetics and T-cell lymphoma
The question. Alterations of epigenetic modifiers are recurrent in T-cell lymphomas, but their causal role in lymphomagenesis remains unclear.
Our approach. We study mutations and expression changes affecting three chromatin complexes, in patient samples and in dedicated mouse models:
- BCL11B — SWI/SNF complex
- JARID2 — PRC2 and SETDB1 complexes
- NCOR1 — NCOR complex
We have developed a panel of ATAC-seq protocols adapted to the material actually available in pathology departments: FAST ATAC-seq on cryopreserved cell suspensions, OMNI ATAC-seq on frozen sections, and ATAC-seq on FFPE sections.
Why it matters. Working on FFPE unlocks retrospective cohorts and routine diagnostic material. The goal is an epigenetic classifier for lymphomas that improves diagnostic accuracy, and the identification of new therapeutic targets.
Axis 2 — Environment and genomic alterations in B-cell lymphoma
The question. How do acquired mutations and environmental exposures combine to drive B-cell lymphomagenesis and treatment resistance?
BTG1 mutations. We showed that BTG1 mutations are prevalent in extranodal DLBCL and associated with MYD88 mutations. Mutant lymphomas display accelerated lymphomagenesis, increased migration and increased mitochondrial mass — and, importantly, increased sensitivity to MCL1 inhibitors, a finding protected by patent WO2023057484A1 (Delage et al., Blood, 2023).
Glyphosate. Starting from epidemiological signals, we test in VavP-BCL2 mice whether glyphosate exposure increases lymphoma risk and chemoresistance, then dissect the mechanism by WGS, ATAC-seq and RNA-seq in ABC (TMD8) and GC (SUDHL4) DLBCL cell lines, with pharmacological screening and systematic comparison to human primary samples.
Why it matters. Both strands run from epidemiology to experimental models and back to the clinic, which is how an exposure signal becomes an actionable therapeutic hypothesis.
Axis 3 — Metabolism and microenvironment in B-cell leukaemia
The question. Paediatric B-ALL often originates in pre-leukaemic clones arising during fetal life. What turns them into overt leukaemia, and what keeps the disease alive at relapse?
Our approach. We study the bone marrow niche — mesenchymal stromal cells, osteoblasts and osteoclasts, arterioles, sinusoids and nerve fibres — and the pro-inflammatory cytokine signalling that links environmental exposure and repeated infections to leukaemogenesis.
Two preliminary results drive the current work:
- MSCs from relapsed patients enhance blast survival, pointing to an active role of the microenvironment in disease maintenance.
- ACLY knock-out produces a block in B-cell differentiation, placing metabolism upstream of the differentiation arrest.
Perspectives. An infection-inducible mouse model, multiplex cytokine-chemokine profiling, and RNA-seq of the niche.
Axis 4 — Inflammation in myeloid malignancies and VEXAS syndrome
The question. Myeloid malignancies and VEXAS syndrome sit at the junction of clonal haematopoiesis and chronic inflammation. Which inflammatory circuits are driving, and which are treatable?
Our approach. We identified the IL-1/IL-1RA axis as differentially activated in monocytic malignancies, and study the inflammasome in that context in collaboration with Thomas Henry. We built the first PDX model of VEXAS, with and without associated MDS, and use it to dissect the mechanism of action of candidate therapeutics — including an industrial collaboration on the preclinical development of JAK inhibitors.
Infectious complications. A dedicated programme addresses the pathophysiology of infection in VEXAS, including a legionellosis programme with the Lyon National Reference Centre and the Legiopath team at CIRI, and the characterisation of EBV-driven T-cell lymphoproliferation with Matthieu Mahevas.
Axis 5 — Immunotherapeutic intervention
The question. CAR-T cells work, but efficacy and toxicity vary widely between patients. What determines the difference, and can new targets widen the reach of the approach?
Our approach. We profile patient material longitudinally — leukapheresis, infusion bag, then blood at days 0, 7 and 14 — by ATAC-seq, to relate the chromatin state of the product and of the circulating cells to clinical outcome. In parallel we generate anti-CD4 CAR-T cells for T-cell malignancies.
Collaborations. M. Sadelain (MSKCC, New York) and O. Hermine (Institut Imagine, Paris).
Transversal axis — Omics, bioinformatics and AI
Every axis above feeds into a shared computational programme, and this is also where our open tools come from.
Technologies. RNA-seq, ATAC-seq, scRNA-seq, scATAC-seq, Cut&Tag and flow cytometry.
Analyses. Differential expression, chromatin accessibility, transcriptome assembly, rearrangements and fusions, epigenetic landscapes, classification markers.
Aims. Cell classification, phenotypic prediction and functional prediction, through workflows built on NMF, random forests, AlphaFold and neural networks.
Part of this work is also published at deepia.org.
Funding
Over 2019-2023 the team raised 5.1 M€ in academic and industrial grants, across 68 grants in which it acted as coordinator for 61.
For 2024-2028, 1.47 M€ is secured and 0.76 M€ applied for:
| Grant | Amount |
|---|---|
| CALYM Carnot Institute | 750 k€ |
| LNCC Innovative cell therapies | 440 k€ |
| bioMérieux | 290 k€ |
| EU EP PerMed | 280 k€ |
| LNCC Team Labeling | 200 k€ |
| CALYM DIAL project | 190 k€ |
| Regional Ligue (two grants) | 80 k€ |
Further support from the Ligue Nationale Contre le Cancer, ANR (FLINOVO), INCa (HR-HC) and AMGEN, with industrial contracts with Servier, AstraZeneca, Roche and Bristol Myers Squibb. The team is a member of the CALYM Carnot Institute and holds one licensed patent.
Collaborations and networks
Academic partners. Gilles Salles, Michel Sadelain, Olivier Hermine, Yenkel Grinberg-Bleyer, Vahid Asnafi, Matthieu Mahevas, Philippe Gaulard, Laurence de Leval, Marco Herling.
Within CIRI. Teams VIRIMI, NOPAB, Legiopath, I2AB, EIA and LYACTS.
Networks and consortia. LYSA, LISA, GBMHM, Société Française d’Hématologie, AssHIB, OncNGS consortium, French VEXAS network.