Chapter 1 Abstract

Acute leukemia is a malignant disorder that arises from the clonal proliferation of leukemic blast cells. The presentation and progression of acute leukemia can vary greatly among different subgroups of patients, and even within the same patient, leukemia cells with different characteristics can coexist. There are two distinct models to understand cellular heterogeneity and cell-of-origin of acute leukemia: the genomic model and the hematopoietic stem cell (HSC) model. Although the genomic model can explain much of the heterogeneity in leukemia, its explanatory power is limited. The HSC model suggests that leukemia is caused by a small population of self-renewing and differentiation-arrested stem cells, while other leukemia cells are their differentiated progeny. Here we introduce HematoMap, an R package that provides a visual representation of the cellular hematopoietic hierarchy of human bone marrow, integrating information from single-cell-based gene expression data to generate a unified model of hematopoietic cell differentiation. By re-analyzing and re-annotating single-cell RNA sequencing data, the project constructed a hierarchy-based reference to interpret normal hematopoiesis cellular compositions and developed a likelihood score to accurately project leukemic blast cells onto the cellular hierarchy of normal hematopoietic differentiation. The article highlights the importance of identifying the cell-of-origin and resolving heterogeneity of acute leukemia to provide critical insights into the pathogenesis of this disease and inform the development of novel therapeutic strategies.