Salt-inducible kinase inhibition sensitizes human acute myeloid leukemia cells to all-trans retinoic acid-induced differentiation.

Differentiation therapies with all-trans retinoic acid (ATRA) have been successful in treating acute promyelocytic leukemia, a rare subtype of acute myeloid leukemia (AML). However, their efficacy is limited in the case of other AML subtypes. Here, we show that the combination of ATRA with salt-inducible kinase (SIK) inhibition significantly enhances ATRA-mediated AML differentiation. SIK inhibition augmented the ability of ATRA to induce growth inhibition and G1 cell cycle arrest of AML cells. Moreover, combining ATRA and SIK inhibition synergistically activated the Akt signaling pathway but not the MAPK pathway. Pharmacological blockade of Akt activity suppressed the combination-induced differentiation, indicating an essential role for Akt in the action of the combination treatment. Taken together, our study reveals a novel role for SIK in the regulation of ATRA-mediated AML differentiation, implicating the combination of ATRA and SIK inhibition as a promising approach for future differentiation therapy.