Abstract
Glucocorticoid (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.
© 2021 by The American Society of Hematology.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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1-Methyl-3-isobutylxanthine / pharmacology
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Animals
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Cell Line, Tumor
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Child
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Chromogranins / antagonists & inhibitors
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Colforsin / pharmacology
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Cyclic AMP / pharmacology
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Cyclic AMP / physiology*
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Dexamethasone / administration & dosage
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Dexamethasone / pharmacology*
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Dinoprostone / administration & dosage
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Dinoprostone / antagonists & inhibitors
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Dinoprostone / pharmacology*
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Dinoprostone / physiology
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Drug Resistance, Neoplasm / genetics
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Drug Resistance, Neoplasm / physiology
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Female
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GTP-Binding Protein alpha Subunits, Gs / antagonists & inhibitors
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GTP-Binding Protein alpha Subunits, Gs / deficiency
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Gene Expression Regulation, Leukemic / drug effects
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Humans
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Male
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Mice
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Models, Animal
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Molecular Targeted Therapy
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
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RNA Interference
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RNA, Small Interfering / genetics
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RNA, Small Interfering / pharmacology
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Radiation Chimera
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Receptors, Glucocorticoid / biosynthesis
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Receptors, Glucocorticoid / genetics
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Receptors, Glucocorticoid / physiology
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Receptors, Prostaglandin E, EP4 Subtype / biosynthesis
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Receptors, Prostaglandin E, EP4 Subtype / genetics
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Second Messenger Systems / drug effects*
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Xenograft Model Antitumor Assays
Substances
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Chromogranins
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NR3C1 protein, human
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NR3C1 protein, mouse
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Neoplasm Proteins
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RNA, Small Interfering
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Receptors, Glucocorticoid
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Receptors, Prostaglandin E, EP4 Subtype
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Colforsin
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Dexamethasone
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Cyclic AMP
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GNAS protein, human
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Gnas protein, mouse
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GTP-Binding Protein alpha Subunits, Gs
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Dinoprostone
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1-Methyl-3-isobutylxanthine