Emmanuelle Clappier’s team – Genomic basis of B-cell acute leukemia

This axis aims to elucidate the oncogenic programs driven by ectopic transcriptional regulators newly identified in our team, in particular in the CDX2/UBTF CEBP/FLT3 high-risk subtype. These lesions activate transcriptional circuits normally silent in B-cell progenitors, generating aberrant subtype-specific dependencies. We investigate how enhancer hijacking or fusion-driven ectopic expression of specific transcription factors reconfigure chromatin states, perturb B-cell developmental trajectories, and create a permissive state for leukemic transformation.

Building on these mechanistic insights, we assess therapeutic susceptibilities in patient-derived xenograft (PDX) models, to validate essential pathways and identify novel therapeutic strategies for these high-risk adult B-ALL.

Building on our demonstration that TP53-mutant and BCR::ABL1-positive clonal hematopoiesis can constitute a preleukemic state for adult B-ALL, this axis investigates how age-related clonal expansions shape leukemogenesis more broadly in adults. Using multi-timepoint and single-cell sequencing, we characterize clonal architecture at diagnosis and its dynamics under treatment pressure. We analyze how these preleukemic states influence genomic and transcriptional programs, MRD clearance, and relapse patterns, thereby shaping disease phenotype and clinical behavior.

Furthermore, by elucidating adult-specific pathways of leukemia initiation and progression, we aim to identify early molecular steps of leukemogenesis and associated biomarkers that could be exploited for early therapeutic intervention.