Team BENAJIBA & LOBRY

Identification and Targeting of Extrinsic and Epigenetic Regulators of Myeloid Hematological Malignancies (ITERM)

The development of innovative translational approaches to identify the key mechanisms underlying the development of acute myeloid leukemia (AML) post-MPN (myeloproliferative neoplasm) is critical to improve clinical outcomes. Leukemic transformation is a complex process with both the intrinsic accumulation of genetic alterations within pre-leukemic cells and the influence of extrinsic factors. These include long-term exposure to prior MPN therapies, as well as the dynamic cellular crosstalk within the bone marrow niche.

Consequently, microenvironmental signals and therapeutic interventions play a critical role in shaping clonal selection and subsequent leukemic transformation. Our goal is to determine whether treatment exposure actively selects for deleterious mutations and to decipher the mechanisms driving this clonal evolution. To comprehensively characterize these mechanisms, our team employs a translational approach integrating clinical database analyses, large-scale functional genomics strategies, and robust in vitro and in vivo models.

In parallel, we are developing innovative in vivo functional screening tools within relevant MPN models to discover and validate novel signaling pathways that participate in leukemic transformation through niche-hematopoiesis interactions.

Additionally, we are evaluating the systemic impact of MPN treatments on non-hematopoietic organs, with a specific focus on the skin. Ultimately, our findings will provide a comprehensive understanding of MPN clonal evolution driven by the tumor microenvironment, paving the way for targeted strategies to prevent leukemic transformation and mitigate disease-associated complications.

AML development is a complex process that is partly dependent on the intrinsic accumulation of genetic alterations within hematopoietic stem cells and progenitors. Recent work has highlighted a key role for the microenvironment in actively supporting leukemic cells and driving treatment resistance.

Our team aims to characterize novel vulnerabilities induced by niche-leukemia interactions. To achieve this, we combine single-cell omics and high-throughput functional screening across physiologically relevant in vitro and in vivo models. Notably, we are developing humanized murine models that faithfully recapitulate the bone marrow microenvironment supporting leukemic cell growth. In parallel, we use transcriptomic, epigenomic, and advanced microscopy approaches to decipher the molecular and cellular mechanisms of niche-leukemia crosstalk. Ultimately, this work aims to pioneer combinatorial therapeutic strategies that simultaneously target leukemic cells and their supportive niche, in order to improve patient survival.

We are establishing a robust validation pipeline for our identified targets. This framework encompasses the preclinical steps required for clinical translation, the discovery of novel response biomarkers, and the evaluation of therapeutic synergies.

Axis 1: Study of Super-Enhancer deregulation in AML pathogenesis.

Super-enhancers (SEs) are characterized by an exceptionally high enrichment of transcriptional coactivators and strong histone tail modifications across isolated or clustered enhancer regions. Defined across virtually all cell types, SEs tend to exhibit high tissue specificity. Notably, leukemic cells frequently display altered gene expression profiles compared to their healthy counterparts.

Intriguingly, SEs tend to be enriched preferentially around oncogenes, driving their aberrant expression. Our results demonstrate that SE profiles and activity are heavily dependent on specific oncogenic alterations; in particular, fusion oncogenes can hijack distinct genomic regions to assemble de novo SEs, thereby inducing oncogene overexpression.

To interrogate SE functionality and its impact on transcriptional regulation and leukemia progression, our team uses genome-wide transcriptomic and epigenomic approaches with high-throughput functional screening platforms, including CRISPR/Cas9, shRNA, and CRISPRi technologies.

Malignant transformation and leukemia progression are marked by profound metabolic reprogramming, driven by key oncogenes and regulatory networks such as MYC. This metabolic-epigenetic relationship is fundamentally bidirectional: the catalytic activity of many epigenetic regulators strictly depends on the availability of intermediary metabolites. Consequently, metabolic dysfunctions directly remodel the gene expression profiles of leukemic cells.

Understanding this functional synergy is critical for uncovering novel therapeutic vulnerabilities. In collaboration with Dr. Puissant’s laboratory, we use complementary in vitro and in vivo models alongside integrated multi-omic approaches to elucidate the complexity of these metabolic-epigenetic mechanisms.

The rapid evolution of high-throughput sequencing and multi-omic technologies has made cancer research increasingly dependent on complex computational biology and bioinformatic analyses. However, implementing these cutting-edge methodologies remains challenging for non-specialist biologists.

To bridge this gap, our team provides technical support and the implementation of advanced omics protocols—including RNA-seq, scRNA-seq, ChIP-seq, and ATAC-seq—alongside high-throughput functional screens (CRISPR/Cas9, shRNA). In parallel, standardized bioinformatic analysis pipelines are being developed to enable researchers to autonomously process and interpret their own multi-omic datasets.