Cell Stem Cell
Volume 25, Issue 2, 1 August 2019, Pages 258-272.e9
Journal home page for Cell Stem Cell

Article
Interconversion between Tumorigenic and Differentiated States in Acute Myeloid Leukemia

https://doi.org/10.1016/j.stem.2019.07.001Get rights and content
Under an Elsevier user license
open archive

Highlights

  • Reversible PU.1 knockdown provides a genetic model of AML differentiation therapy

  • Mature AML-derived cells can revert to a leukemogenic state upon PU.1 suppression

  • Mouse and human APL cells can regain clonogenicity after ATRA-induced differentiation

Summary

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.

Keywords

acute myeloid leukemia
differentiation therapy
cancer stem cell
leukemia stem cell
myelopoiesis
PU.1
transcription factor
acute promyelocytic leukemia
retinoic acid
pioneer factor

Cited by (0)

23

Present address: INSERM U1037, Centre de Recherches en Cancérologie de Toulouse, 2 Avenue Hubert Curien, 31037 Toulouse, France

24

These authors contributed equally

25

Lead Contact