Serine/glycine synthesis addiction in acute lymphoblastic leukemia and resulting therapeutic opportunities

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Despite the tremendous increase in overall survival in children, relapse and long-term toxic side-effects of the current therapies still remain major drawbacks. Whereas most healthy cells take up serine and glycine from their environment, some cancer cells activate endogenous serine/glycine production and become addicted to this pathway to support their proliferation. The host lab previously identified two genetics lesions (the RPL10 R98S mutation and NKX2- 1 transcription factor overexpression) that induce serine/glycine synthesis dependence in ALL, allowing delineation of patients benefiting therapeutics targeting this serine/glycine synthesis addiction. Preliminary data support that also loss of transcription factor IKZF1 results in serine/glycine synthesis addiction in ALL. Therefore, we aim to investigate, both in cell and animal models, whether loss of IKZF1 in ALL also defines a serine/glycine synthesis addicted cancer subgroup. Furthermore, the antidepressant sertraline inhibits serine/glycine synthesis enzyme SHMT1/2. Hence, we aim to improve current ALL therapy by exploring combination therapies of conventional chemotherapies or novel agents with sertraline in serine/glycine addicted ALL cell models and PDX mouse models, with the ultimate goal to target ALL cells more specifically, improve therapy efficacy and reduce toxicity, relapse and even therapy failure.