AML Differentiation Plasticity May Contribute to Relapse

Tumorigenic cancer stem cells (CSC) are important in acute myeloid leukemia (AML) and other malignancies, and therapies intended to eliminate them or promote their differentiation, such as FLT3 inhibitors and mutant IDH1/2 inhibitors, have recently entered the clinic. The pioneer transcription factor PU.1 (SPI1) is required for normal myelopoiesis and for AML differentiation caused by treatment with all-trans retinoic acid (ATRA) or LSD1 inhibitors, and a reduction in PU.1 activity is common in AML. McKenzie, Ghisi, Oxley, and colleagues found that PU.1 knockdown drove AML development in a mouse model of p53-deficient AML and that restoration of PU.1 led to leukemia differentiation and remission. Suppression of PU.1 in differentiated AML-derived cells caused them to dedifferentiate back to a clonogenic, leukemogenic state, indicating that their maturation was reversible. Chromatin accessibility and the expression of myeloid maturation genes was regulated by PU.1, and PU.1′s continuous presence at regulatory elements was essential to maintain a differentiated state in mature AML-derived cells. In a mouse model of acute promyelocytic leukemia (APL), discontinuation of ATRA reverted mature APL cells to leukemogenic states, and differentiation of human APL cells triggered by ATRA was also reversible after cessation of therapy. These results suggest that eliminating tumor cells at all stages of maturation may be important to achieve full AML cures.

McKenzie MD, Ghisi M, Oxley EP, Ngo S, Cimmino L, Esnault C, et al. Interconversion between tumorigenic and differentiated states in acute myeloid leukemia. Cell Stem Cell 2019;25:258–72.E9.

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