Grant Number:	1R01CA315128-01 Interpret this number
Primary Investigator:	Teachey, David
Organization:	Children'S Hosp Of Philadelphia
Project Title:	The Impact of Genetic Ancestry on Notch1 Activation and Signaling in T-All
Fiscal Year:	2026

PROJECT SUMMARY/ABSTRACT Outcomes for children and young adults with relapsed T-cell acute lymphoblastic leukemia (T-ALL) remain poor. A critical unmet need is the identification of patients with T-ALL at risk for relapse in order to allocate them to novel therapies and prevent relapse. To address this, we performed one of the largest and most comprehensive genomic profiling studies of T-ALL and found 1) T-ALL can be classified into 15 molecular subtypes with distinct prognosis, 2) over 60% of leukemic drivers in T-ALL are located in non-coding regions, and 3) most importantly, we discovered striking differences in the frequency and prognostic significance of T-ALL genomic drivers across genetic ancestries. It is critical to characterize the biology underlying the interactions between ancestry and leukemia genomics prior to implementing T-ALL genomics-based risk stratification in the clinic to ensure all patients benefit. Most notably, we discovered that 1) NOTCH1 mutations, the most common somatic genetic alterations in T-ALL, have distinct prognostic value by ancestry: gain-of-function NOTCH1 mutations were associated with favorable outcome in European Americans (EA) but had no prognostic impact in African American (AA) children; 2) NOTCH1 signaling activity was generally lower in AAs than EAs, regardless of somatic mutations in this gene. It remains unknown what is the biological basis for the differential NOTCH1 activity and why this impacts outcomes. If NOTCH1 mutations were used to risk-stratify children with T-ALL, many AA children would be mis-classified as having good prognosis. We will study ancestry-related biological differences in T-ALL, focusing on NOTCH1 signaling. A unique strength is our molecular profiling cohort of 1,810 T-ALL cases from NCTN clinical trials AALL0434 and AALL1231. Prior NCI investment enabled us to generate WGS/WTS (n=1810 cases), epigenomics (n=235), proteomics (n=100), ex vivo drug profiling (n=84), and patient derived xenograft (PDX) models (n=143). Leveraging our unique access to patient samples, we will expand and develop an EA and an AA T-ALL dataset having >200 cases with epigenomic, genomic, proteomic and drug sensitivity profiling data. Our central hypothesis is that a combination of genetic and non-genetic differences between EAs and AAs dictate NOTCH1 activation in T-ALL with differential impact on prognosis, chemoresistance, and response to therapy. We will test this hypothesis with the following specific aims: 1) Define the biological mechanisms underlying differential NOTCH1 activation in T-ALL in EAs vs AAs; 2) Determine how NOTCH1 signaling impacts T-ALL sensitivity to cytotoxic and targeted therapeutics; and, 3) Develop ancestry- inclusive risk classifiers for T-ALL using artificial intelligence. The results of this work will provide insights into T- ALL leukemogenesis, especially in the context of NOTCH1 signaling. It will define the mechanisms underlying the differential prognostic impact of genetic alterations based on ancestry, allowing for the identification of ancestry-inclusive targeted therapeutics and development of ancestry-inclusive risk classifiers. Taking solution- oriented approaches, the goal of this work is to improve outcomes for all patients with T-ALL.





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