2013
DOI: 10.1182/blood-2013-03-489468
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PPARα and fatty acid oxidation mediate glucocorticoid resistance in chronic lymphocytic leukemia

Abstract: Key Points• Glucocorticoids downregulate PKM2 and metabolism in CLL cells, impairing access to bioenergetic programs needed to repair cell damage.• PPARa and fatty acid oxidation antagonists potentiate the cytotoxic effects of glucocorticoids.High-dose glucocorticoids (GCs) can be a useful treatment for aggressive forms of chronic lymphocytic leukemia (CLL). However, their mechanism of action is not well understood, and resistance to GCs is inevitable. In a minimal, serum-free culture system, the synthetic GC … Show more

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Cited by 86 publications
(81 citation statements)
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“…PPARα was previously shown to mediate protection of CLL cells from harsh microenvironmental conditions, including the presence of cytotoxic agents (23,30). This result suggests that PPARα plays a role in CLL cell viability.…”
Section: Pparα Antagonist Is Cytotoxic To Cll Cells Even In the Presesupporting
confidence: 60%
See 1 more Smart Citation
“…PPARα was previously shown to mediate protection of CLL cells from harsh microenvironmental conditions, including the presence of cytotoxic agents (23,30). This result suggests that PPARα plays a role in CLL cell viability.…”
Section: Pparα Antagonist Is Cytotoxic To Cll Cells Even In the Presesupporting
confidence: 60%
“…PPARα is overexpressed in CLL cells and helps to protect them from harsh microenvironmental conditions. MK886, a small molecule that is reported to have PPARα antagonist properties, exhibits anti-CLL activity in vitro and in vivo (23,30 (Figures 2, 3), but was less cytotoxic to B cells isolated from healthy volunteers ( Supplementary Figure S1). Because accessory cells can rescue CLL cells from spontaneous and drug-induced apoptosis (43)(44)(45), as well as protect CLL cells from fludarabineinduced apoptosis in vitro (31), it is essential to evaluate potential therapeutics in CLL accessory cell cocultures.…”
Section: Discussionmentioning
confidence: 99%
“…Some kinases or their activators can also lead to specific inhibition of PPAR transcriptional activity, such as the MEK1 or AMP-activated protein kinase activators 5-aminoimidazole-4-carboxamide riboside [26,27]. Furthermore, it was shown very recently that PPAR inhibition could improve the therapeutic efficacy of glucocorticoids in aggressive forms of chronic lymphocytic leukemia [28]. Thus, PPAR inhibition could be used in V9V2 T cell-based cancer immunotherapy.…”
Section: Resultsmentioning
confidence: 99%
“…Quantification of specific RNA transcripts was performed as before 20 with the primers listed in supplemental Figure 9.…”
Section: Quantitative Reverse Transcription-polymerase Chain Reactionmentioning
confidence: 99%