Characterization and targeting of HSPC-like blasts in high-risk leukemias

About This Grant

PROJECT SUMMARY Acute leukemias are the most common pediatric cancers, exhibiting significant variability in treatment response and relapse rates among genomic subtypes. A major challenge in treatment is the presence of leukemic-initiating cells that are resistant to therapy. While these cells were first discovered in acute myeloid leukemia, their role in other types of acute leukemia remains poorly understood. Recent studies have uncovered a neoplastic population of hematopoietic stem and progenitor cell-like (HSPC-like) blast in high-risk subtypes of acute lymphoblastic leukemia. These HSPC-like blasts are molecularly heterogeneous and linked to treatment resistance and poor outcomes. This study aims to investigate the molecular characteristics and clinical implications of HSPC-like blasts across major high-risk leukemia subtypes, including myeloid, lymphoblastic, and mixed-lineage leukemias. Our goal is to uncover common, targetable mechanisms of treatment failure and to develop therapeutic strategies that specifically target these cells. Using single-cell multiomics and patient samples, we will identify the mutational and transcriptomic signatures and define gene regulatory networks using novel network biology algorithms. We will determine the prognostic significance of HSPC-like signatures and explore therapeutic strategies through ex vivo drug screening and in vivo validation in PDX models. Because primary human leukemic blasts are a scarce, patient-limited resource, expansion in immunodeficient mice yields the millions of cells needed for ex vivo drug testing, in vivo therapeutic studies, and mechanistic analyses.