Abstract
Glucorticoids (GCs) such as dexamethasone (DEX) remain important treatments for Chronic Lymphocytic Leukemia (CLL) but the mechanisms are poorly understood and resistance is inevitable. Proliferation centers (PC) in lymph nodes and bone marrow offer protection against many cytotoxic drugs and circulating CLL cells were found to acquire resistance to DEX-mediated killing in conditions encountered in PCs including stimulation by toll-like receptor agonists and interactions with stromal cells. The resistant state was associated with impaired glucocorticoid receptor-mediated gene expression, autocrine activation of STAT3 through Janus Kinases (JAKs), and increased glycolysis. The JAK1/2 inhibitor ruxolitinib blocked STAT3-phosphorylation and partially improved DEX-mediated killing of stimulated CLL cells in vitro but not in CLL patients in vivo. An automated microscopy-based screen of a kinase inhibitor library implicated an additional protective role for the PI3K/AKT/FOXO pathway. Blocking this pathway with the glycolysis inhibitor 2-deoxyglucose (2-DG) or the PI3K-inhibitors idelalisib and buparlisib increased DEX-mediated killing but did not block STAT3-phosphorylation. Combining idelalisib or buparlisib with ruxolitinib greatly increased killing by DEX. These observations suggest that glucocorticoid resistance in CLL cells may be overcome by combining JAK and PI3K inhibitors.
Highlights
High-dose glucocorticoids (HDGCs) are a useful treatment modality for Chronic Lymphocytic Leukemia (CLL) even in the era of novel agents [1,2]
Stimulated CLL cells resist glucocorticoidmediated transcriptional death Unstimulated CLL cells are killed by glucocorticoids such as DEX following a program of atrophy involving down-regulation of PKM2 activity and decreased glycolysis [4]
CLL cells stimulated with IL2 and resiquimod (2S) [11, 12, 19] are resistant to DEX-mediated killing at a dose of 30 μM that approximates plasma levels following HDGCs (Figure 1a, left panel) [2, 4]
Summary
High-dose glucocorticoids (HDGCs) are a useful treatment modality for CLL even in the era of novel agents [1,2]. In circulating CLL cells, glucocorticoids (GCs) activate a transcriptional program that leads to atrophy and death subsequent to decreased glycolysis from down-regulated pyruvate kinase (PK) M2 expression and function [4]. CLL cells in these microenvironments divide in response to stimulation from signals such as antigens, costimulatory molecules, toll-like receptor (TLR) ligands, chemokines, and cytokines produced by T, nurse, stromal, and other CLL cells. These supportive microenvironments are sanctuaries that allow CLL cells to resist cytotoxic drugs [6, 7] but little is known about their effects on responses to GCs
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