Work

Signaling mechanisms that regulate ex vivo survival of human acute myeloid leukemia initiating cells

Year: 2017

Type: article

Abstract: Acute myeloid leukemia (AML) is an aggressive malignancy of the hematopoietic system that arises through clonal expansion of myeloid precursor cells that have arrested at an early stage of differentiation and ultimately causes death in over 50% of patients. Despite the aggressive growth characteristics of AML in vivo, AML blasts are difficult to culture once removed from the patient, suggesting that AML cells depend on signals from the microenvironment 1 , 2 . AML initiating cells (LICs), defined functionally as cells capable of initiating AML in immunocompromised mice 3 , are also challenging to maintain in culture, presenting a major obstacle to developing new therapies for AML that target the LIC. Co-culture with stromal cells 4 , 5 , 6 can maintain and expand LICs; however these culture systems use multiple cytokines that may promote differentiation and loss of LICs ex vivo. Small molecules such as SR1 (an aryl-hydrocarbon receptor antagonist) and UM729 support AML viability without stromal co-culture, but also require multiple cytokines 1 . In this work, we demonstrate an alternative approach that enhances the viability of primary AML cells and supports ex vivo maintenance of LICs in cytokine-free medium. We show that inhibition of GSK-3, which activates Wnt signaling, markedly improves the viability of primary human AML cells in cytokine-free medium and further that combined inhibition of GSK-3 and the nutrient sensor mTORC1 maintains LICs capable of engrafting immunocompromised mice, identifying a signaling network that regulates the viability of LICs.

Source: Blood Cancer Journal

DOI: 10.1038/s41408-017-0003-1