Figure 8.

miR-126 Represses Multiple AKT Inputs in LSC

LSC express high endogenous levels of miR-126 compared with more differentiated AML populations. High levels of endogenous or experimental miR-126 repress the level of several proteins regulating AKT (PI3K signaling, PI3CD, PIK3R2; integrin signaling, ADAM9, ITGA6, ILK, PARVB; RTK signaling, CRK, ABI1, CD97, CD84; MTOR signaling, MAPKAP1), reducing overall AKT levels and activity. Furthermore, high levels of miR-126 reduce pPDK1 Ser²⁴¹, which phosphorylates AKT, and MAPKAP1, which is required for MTORC2 formation and full activation of AKT. Significantly diminished levels of AKT activity preferentially retain LSC in a quiescent state by increasing p27 levels, together with miR-126 targeted reduction of CDK3. Under high miR-126 levels, LSC that do enter the cycle are biased toward a self-renewal division. Reduction of LSC miR-126 levels through currently unspecified developmental cues (or lentiviral sponge-mediated) de-represses the expression and activity of multiple AKT signaling inputs. LSC now preferentially cycle and are biased toward differentiation divisions.