RT Journal Article
SR Electronic
T1 The Hepatic Microenvironment Uniquely Protects Leukemia Cells through Induction of Growth and Survival Pathways Mediated by LIPG
JF Cancer Discovery
JO Cancer Discov
FD American Association for Cancer Research
DO 10.1158/2159-8290.CD-20-0318
A1 Ye, Haobin
A1 Minhajuddin, Mohammad
A1 Krug, Anna
A1 Pei, Shanshan
A1 Chou, Chih-Hsing
A1 Culp-Hill, Rachel
A1 Ponder, Jessica
A1 De Bloois, Erik
A1 Schniedewind, Björn
A1 Amaya, Maria L.
A1 Inguva, Anagha
A1 Stevens, Brett M.
A1 Pollyea, Daniel A.
A1 Christians, Uwe
A1 Grimes, H. Leighton
A1 D'Alessandro, Angelo
A1 Jordan, Craig T.
YR 2020
UL http://cancerdiscovery.aacrjournals.org/content/early/2021/01/18/2159-8290.CD-20-0318.abstract
AB Due to the disseminated nature of leukemia, malignant cells are exposed to many different tissue microenvironments, including a variety of extramedullary sites. In the present study, we demonstrate that leukemic cells residing in the liver display unique biological properties and also contribute to systemic changes that influence physiologic responses to chemotherapy. Specifically, the liver microenvironment induces metabolic adaptations via upregulating expression of endothelial lipase in leukemia cells, which not only stimulates tumor cell proliferation through polyunsaturated fatty acid–mediated pathways, but also promotes survival by stabilizing antiapoptotic proteins. Additionally, hepatic infiltration and tissue damage caused by malignant cells induces release of liver-derived enzymes capable of degrading chemotherapy drugs, an event that further protects leukemia cells from conventional therapies. Together, these studies demonstrate a unique role for liver in modulating the pathogenesis of leukemic disease and suggest that the hepatic microenvironment may protect leukemia cells from chemotherapeutic challenge.Significance: The studies presented herein demonstrate that the liver provides a microenvironment in which leukemia cells acquire unique metabolic properties. The adaptations that occur in the liver confer increased resistance to chemotherapy. Therefore, we propose that therapies designed to overcome liver-specific metabolic changes will yield improved outcomes for patients with leukemia.