Prostaglandin E2 stimulates cAMP signaling and resensitizes human leukemia cells to glucocorticoid-induced cell death
AuthorsRoderick, Justine E
Gallagher, Kayleigh M
Murphy, Leonard C
O'Connor, Kevin W
Brehm, Michael A
Greiner, Dale L
Zhu, Lihua Julie
Green, Michael R.
Kelliher, Michelle A
UMass Chan AffiliationsMedicine
Molecular, Cell and Cancer Biology
Morningside Graduate School of Biomedical Sciences
Program in Molecular Medicine
Document TypeJournal Article
MetadataShow full item record
AbstractGlucocorticoid (GC) resistance remains a clinical challenge in pediatric acute lymphoblastic leukemia where response to GC is a reliable prognostic indicator. To identify GC resistance pathways, we conducted a genome-wide, survival-based, short hairpin RNA screen in murine T-cell acute lymphoblastic leukemia (T-ALL) cells. Genes identified in the screen interfere with cyclic adenosine monophosphate (cAMP) signaling and are underexpressed in GC-resistant or relapsed ALL patients. Silencing of the cAMP-activating Gnas gene interfered with GC-induced gene expression, resulting in dexamethasone resistance in vitro and in vivo. We demonstrate that cAMP signaling synergizes with dexamethasone to enhance cell death in GC-resistant human T-ALL cells. We find the E prostanoid receptor 4 expressed in T-ALL samples and demonstrate that prostaglandin E2 (PGE2) increases intracellular cAMP, potentiates GC-induced gene expression, and sensitizes human T-ALL samples to dexamethasone in vitro and in vivo. These findings identify PGE2 as a target for GC resensitization in relapsed pediatric T-ALL.
SourceRoderick JE, Gallagher KM, Murphy LC, O'Connor KW, Tang K, Zhang B, Brehm MA, Greiner DL, Yu J, Zhu LJ, Green MR, Kelliher MA. Prostaglandin E2 stimulates cAMP signaling and resensitizes human leukemia cells to glucocorticoid-induced cell death. Blood. 2021 Jan 28;137(4):500-512. doi: 10.1182/blood.2020005712. PMID: 33507291; PMCID: PMC7845005.
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/51749
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