Analysis of Developmental Arrest and Treatment Resistance in High-risk T-ALL

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Project Summary Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, accounting for nearly 1 in 3 new pediatric cancer diagnoses. Though mortality and morbidity associated with common ALL subtypes have drastically improved as a result of advances in chemotherapy and risk stratification, high rates of treatment failure persist in understudied subtypes of ALL, such as early T-cell precursor acute lymphoblastic leukemia (ETP-ALL). ETP-ALL patients fail the first month of chemotherapy at 7.7x the rate of non-ETP ALL patients and are twice as likely to have detectable residual disease at end of induction chemotherapy. We hypothesize that these striking differences in response to treatment are intrinsically rooted in biological characteristics of ETP-ALL, which can be further revealed using high-throughput measurement tools, such as single-cell genomics. The completion of COG’s AALL00344 clinical trial, which enrolled 325 ETP-ALL patients, represents an exciting opportunity to improve our understanding of ETP-ALL and identify the biological reasons for treatment failure. In Aim 1, we will use single cell transcriptomics and single cell chromatin accessibility to investigate clonal diversity, transcriptomic features and epigenetic signatures in 30 patients with ETP-ALL. We will seek to place ETP-ALL blasts in context of healthy T-cell development and other pediatric leukemias. In Aim 2, we will compare ETP- ALL patients based on clinical response and use patient-specific xenograph models to functionally perturb genes and pathways enriched in non-responding patients. Our project is poised to synergize with bulk sequencing data being generated for 325 ETP-ALL patients through an NIH X01 grant (HD100702-01), specifically due to our ability to deconvolute bulk sequencing data using subclone-specific signatures discovered in single cell data. We believe the proposed work can help to elucidate the genetic drivers of ETP-ALL and identify targets and cell populations associated with treatment failure, thus significantly impacting the diagnosis and treatment of ETP- ALL.