Generation of preclinical models and integrated molecular characterization

The Cellot lab have optimized a pipeline to generate unique human models of megakaryocytic AML, or AMKL, providing physiologically relevant substrate to study a disease affecting infants and associated with dismal outcomes.

Pediatric AMKL is a molecularly heterogeneous disease often driven by potent chimeric fusion oncogenes and genotype-specific innovative therapies are critically needed to overcome the stagnating cure rates.

Building on our expertise in stem cell biology, we overexpressed the NUP98-KDM5A fusion oncogene in cord blood stem/progenitor cells (HSPCs) to engineer the first human AMKL models that phenocopy human disease in immunodeficient mice (Blood Adv 2019; 3 (21): 3307–3321).

Using molecular approaches (RNAseq, cell surface proteomics) and integrative bioinformatic analyses, we uncovered novel disease biomarkers, with clinical application for diagnostics and disease monitoring, and importantly, identified therapeutic vulnerabilities we are actively pursuing.

Currently, we are developing human models of CBFA2T3-GLIS2 AMKL and other high-risk leukemias and establishing a pipeline for novel targeted therapeutics.

Funding: CCSRI-Cole Foundation Impact grant; S. Cellot co-PI, B.T. Wilhelm, C. Eaves & F. Barabé; 2017-2022.