The Role of Proteostasis Pathways in Pediatric Leukemia

Childhood Cancers

Robert Signer, PhD (UC San Diego)

Helena Yu, MD (UC San Diego)

Despite excellent outcomes for many children with B-cell acute lymphoblastic leukemia (B-ALL), infants with B-ALL remain difficult to cure. During physiologic development, fetal HSCs activate the heat shock response through heat shock factor 1 (Hsf1) to maintain protein homeostasis (proteostasis) and HSC function. However, we found that in some contexts, pre-leukemic can co-opt this adaptive mechanism to resist stress and fuel clonal expansion and leukemia. This raises the question of whether normal developmental activation of Hsf1 is hijacked to promote the development of infant B-ALL. In this proposal, we will test the hypothesis that Hsf1 promotes initiation and progression of infant B-ALL by promoting proteostasis. Additionally, we will evaluate the impact of Hsf1 on gene expression programs in B-ALL. These studies will reveal whether Hsf1-driven fetal hematopoietic programs preferentially influence the onset of infant B-ALL, with the potential to reveal a new therapeutic target.