Interconversion between Tumorigenic and Differentiated States in Acute Myeloid Leukemia

Abstract

Tumors are composed of phenotypically heterogeneous cancer cells that often resemble various differentiation states of their lineage of origin. Within this hierarchy, it is thought that an immature subpopulation of tumor-propagating cancer stem cells (CSCs) differentiates into non-tumorigenic progeny, providing a rationale for therapeutic strategies that specifically eradicate CSCs or induce their differentiation. The clinical success of these approaches depends on CSC differentiation being unidirectional rather than reversible, yet this question remains unresolved even in prototypically hierarchical malignancies, such as acute myeloid leukemia (AML). Here, we show in murine and human models of AML that, upon perturbation of endogenous expression of the lineage-determining transcription factor PU.1 or withdrawal of established differentiation therapies, some mature leukemia cells can de-differentiate and reacquire clonogenic and leukemogenic properties. Our results reveal plasticity of CSC maturation in AML, highlighting the need to therapeutically eradicate cancer cells across a range of differentiation states. Intratumoral phenotypic heterogeneity in acute myeloid leukemia (AML) and many other cancers is thought to follow a hierarchical cancer stem cell model. Dickins and colleagues show here that mature, non-leukemogenic AML cells can reacquire leukemia-initiating activity and promote disease progression through de-differentiation.