Sex-bias in pediatric T-cell acute lymphoblastic leukemia; towards targeted therapy and precision medicine

Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy with a pronounced sex-bias (~71% male).Based on my striking preliminary results I hypothesize that genes on both sex chromosomes contribute to T-ALL sex-bias and may offer novel avenues for therapeutic action and sex-specific risk classification.

Here, I will (AIM 1) reveal the dynamics of X-chromosome inactivation during human T-cell development, and further use this data to test the potential of (AIM 2) sex-specific risk classification in T-ALL and (AIM 3) Y-chromosome oncogenes as targets for therapy in T-ALL.Specifically, I will use exome, methylome and single-cell RNA-seq of T-cell sub-populations isolated from healthy pediatric thymi to map patterns of X-inactivation and Y-chromosome gene expression at each stage of T-cell development from which T-ALL arises.

Using my cutting-edge bioinformatics approaches I will use this data to guide sex-specific molecular risk classification of T-ALL and test associations with key clinical outcomes.

In parallel, genetic and pharmacological interventions in transformed and primary T-ALL cells as well as xenotransplantation experiments in mouse models will test the function and therapeutic potential of Y-chromosome oncogenes.My approach holds promise for delivering novel clinical alternatives to improve prognosis for children with T-ALL.

More broadly, my results will serve as a foundation for further studies of sex-bias in malignant disease.