Molecular Mechanisms and Underlying Heterogeneity in Acute Lymphoblastic Leukemia

Abstract

Hematopoiesis is a highly orchestrated process that culminates in the production of functionally heterogeneous blood cell types. Leukemogenesis is the disruption of this process by stochastic and dynamic molecular alterations to produce highly malignant cell types. In my work, I have focused on acute lymphoblastic leukemia (ALL), as it is the most frequent neoplasm in children, adolescents and young adults and a particularly aggressive disease. Our understanding of the processes that direct blood cell development and malignant transformation have been made possible by a variety of animal models, most notably the zebrafish. Zebrafish are a useful model to study normal and malignant hematopoiesis due to their unique characteristics including close homology to humans, rapid development, transparency, and ease of transgenic generation for cell lineage tracing. In this thesis, I have transcriptionally profiled normal, aberrant, and malignant hematopoietic cells from zebrafish at the single-cell level to define the major blood cell types, discovered a novel Natural Killer cell type, and identified that Myc-induced T-ALL are arrested at the CD4+/CD8+ cortical thymocyte stage of development. I also discovered strain differences in zebrafish that produced new models of B-ALL and bi-phenotypic B/T-ALL. This work revealed underlying roles of cell lineage, rather than initiating oncogenic driver, in regulating leukemia aggression, latency of regrowth and cancer stem cell number, likely accounting for why T-ALLs are more aggressive that B-ALLs. Finally, I uncovered a role of the oncogenic phosphatase PRL3 in driving T-ALL initiation and maintenance. My work identified that PRL3 suppresses T cell signaling pathways by dampening the activity of key proteins required for signaling transduction, including VAV1. I went on to validate the mechanistic influence of PRL3 on VAV1 and found that inhibition of PRL3 leads to elevated GEF activity of VAV1 and subsequently induces apoptosis. In total, my work revealed that PRL3 is not only important in T-ALL initiation, but showed that PRL3 is critical for the maintenance of T-ALL and is a novel therapeutic target in this disease.