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Pediatric B-cell precursor acute lymphoblastic leukemia outcomes and survival have improved in the last decades, but unmet medical needs remain for this complex disease state and research is ongoing to address the underlying molecular basis. While it is known that B cell clones carrying canonical mutations are present in asymptomatic individuals, there are currently no methods to both predict who will develop blood lymphoid cancer as they age and to know how to intercept it. Thus, at the heart of this research project lies the vision of applying highly conceptually and technically innovative approaches to tackle a fundamental clinical challenge – identifying and subsequently targeting aberrant B cell clones in patients at risk for cancerous transformation. Based on recent evidence, we hypothesize that a combination of cell-intrinsic and micro-environmental epigenetic cues configure the ‘tipping point’ at which self-reactive B cells acquire the necessary potential and trajectory constraints to promote disease progression and/or undergo malignant transformation. Using murine models that faithfully mimic childhood leukemia, we will identify the epigenetic remodeling events of hematopoietic but also of stromal supportive cells (such as mesenchymal stromal cells) that could both participate to promote the transition to a leukemic stage. We will further characterize the impact of direct (epi)genetic alterations on these aberrant clones and their pathogenic trajectories. Finally, we will investigate how different environmental exposure could perturb this dialogue and contribute to the pre-leukemic conversion to a leukemic ongoing process. This will help identify clinically translatable epigenetic biomarkers and signatures for mutated clonal B cells to help predict disease outcomes, including cancerous transformation. By zooming into mutated pathogenic B cell subpopulations, our novel approach also conveys great potential to identify new epigenetic targets and pathways for the early identification of clones associated with leukemia pathogenesis, forming the basis for early ‘window-of-opportunity’ interdiction strategies. This represents a paradigm shift for the field, helping us to move to a future where we could identify and target potential aggressive leukemias by intervening at their earliest detection before they become an intractable clinical challenge. Achieving the prevention of the development of leukemia should lead to a substantial increase in child survival rates and might also open new avenues to a reduction in the complications arising for the late-effects of current treatments. We anticipate that the technologies and findings generated in this work will also be applicable across other hematological disorders, yielding novel conceptual frameworks to address the central challenge of malignant transformation and tumor evolution.