Mutant NRASG12V drives acute myeloid leukemia (AML) cell proliferation and self-renewal in a mutually exclusive manner. Previous studies demonstrated that AML cell proliferation and self-renewal are associated with differential NRASG12V transcript levels, but whether different NRASG12V protein levels dictate proliferative versus self-renewal phenotypes is not known. To address that knowledge gap, Kurata and colleagues engineered AML cell lines in which tetracycline-inducible NRASG12V expression levels are tunable using various doxycycline doses. The authors found that moderate NRASG12V protein expression promotes AML cell proliferation, whereas higher NRASG12V protein expression facilitates AML cell senescence and self-renewal. Using mass cytometry, the authors showed that abundances of several downstream NRASG12V effectors, including known stemness mediators such as β-catenin, increase in a dose-dependent fashion, whereas others, such as phosphorylated STAT1, are not dose-dependent. Overall, this study demonstrates that differential NRASG12V protein levels disparately drive AML cell proliferation and...

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