HSPC-like blasts in acute lymphoblastic leukemia: biology and therapeutic opportunities

Stem cell-like blasts have been associated with hierarchical tumor-initiating potential and poor outcomes in myeloid leukemias. Previous studies using primary samples of acute lymphoblastic leukemia (ALL) have identified blasts that immunophenotypically and transcriptomically resemble hematopoietic stem and progenitor cells (HSPCs), but failed to consistently demonstrate hierarchical tumor-initiating potential in xenograft models. Recent multi-omic profiling of lymphoblastic and mixed-phenotype leukemias has improved our understanding of the phenotypes of HSPC-like blasts and their association with treatment failure, relapse, and lineage switch during therapy. In this review, we highlight the opportunities and challenges of using HSPC-like blasts to risk-stratify patients with ALL and direct patients with relapsed/refractory disease toward targeted therapies.