Similarly, hyperactivation of PI3K/AKT signaling in mouse models by inactivation of downstream negative regulators such as Pten, Pml, GSK3β (Yilmaz et al, 2006; Perry et al, 2011; Ito et al, 2012), and FoxO (Tothova et al, 2007) results in a transient increase in activated HSCs and has been reported to be accompanied by exhaustion, impaired repopulation capacity, or leukemia (Yilmaz et al, 2006). This evidence concerns the gene PML and leukemia.