Despite high rates of initial response to frontline treatment in many human cancers, mortality largely results from relapse or metastasis. Diverse clinical responses are considered to be the result of intratumoral diversity: all cells within a given tumor do not possess the same behavior or response to therapy. Understanding tumor heterogeneity is key to improving outcomes for patients with cancer. Although debate remains as to whether cells with treatment resistance exist as part of the initial tumor at presentation versus develop under the pressure of therapy, many studies suggest it to be the former. Further, this intrinsic heterogeneity observed in primary tissues is not accurately represented or studied through genetic animal models or cell lines and does not lend itself to study of bulk tumor cells. Understanding the intrinsic heterogeneity of tumor populations, specifically here, leukemia populations, will improve the ability for clinicians to make prognosis and treatment decisions for patients. This requires using single-cell studies to identify risk-associated individual leukemia populations across patients.

To organize single-cell data from primary patient samples, we have taken a developmental view of acute lymphoblastic leukemia. We consider the development of leukemia in children or young adults as a process of misguided differentiation. As children grow, tissues go through specific developmental programs characterized by periods of growth and proliferation, creating rich environments for genetic or non-genetic dysregulation, and the development of cancer. It is not surprising, therefore, that acute lymphoblastic leukemia most often occurs in children while the immune system is encountering, and countering, many novel antigens driving cellular immune diversity. But key to understanding the molecular and mechanistic causes of these aberrant developmental trajectories is a detailed understanding of the developmental context of the tumor tissue of origin. Thus, we are interested in both the normal developmental process of blood cells but also the aberrant development that leads to leukemia.