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. 2018 Nov;59(11):2686-2691.
doi: 10.1080/10428194.2018.1439167. Epub 2018 Feb 21.

Ibrutinib inhibits free fatty acid metabolism in chronic lymphocytic leukemia

Uri Rozovski  1   2 , David M Harris  1 , Ping Li  1 , Zhiming Liu  1 , Preetesh Jain  1 , Alessandra Ferrajoli  1 , Jan Burger  1 , Phillip Thompson  1 , Nitin Jain  1 , William Wierda  1 , Michael J Keating  1 , Zeev Estrov  1
Affiliations

Ibrutinib inhibits free fatty acid metabolism in chronic lymphocytic leukemia

Uri Rozovski et al. Leuk Lymphoma. 2018 Nov.

Abstract

Unlike normal B-cells, and similar to fat cells, chronic lymphocytic leukemia (CLL) cells aberrantly express lipoprotein lipase (LPL), which contributes to free fatty acids (FFAs) metabolism. Here we show that, in CLL cells, the B-cell receptor (BCR) inhibitor ibrutinib reduced LPL mRNA and protein levels and inhibited FFA metabolism in vitro. Likewise, in CLL cells from ibrutinib-treated patients, FFA metabolism was reduced and eventually stopped. Because ibrutinib disrupts CLL cells' ability to use FFAs for energy production, and because various BCR-dependent cellular functions rely on a continuous supply of chemical energy, ibrutinib interrupts several pathways imperative for cellular function in CLL cells.

Keywords: CLL; ibrutinib; lipoprotein lipase; metabolism.

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Conflict of interest statement

Disclosure statement

Alessandra Ferrajoli, Jan Burger, Phillip Thompson, Nitin Jain,William Wierda, Michael J. Keating and Zeev Estrov received honoraria from pharmacyclics.

Uri Rozovski, David M. Harris, Ping Li, Zhiming Liu, Preetesh Jain report no conflicts of interest.

Figures

Fig 1.
Fig 1.
Ibrutinib inhibits palmitic acid-dependent metabolism of chronic lymphocytic leukemia (CLL) cells in vitro. CLL cells were incubated for 48 hours in sealed tissue culture flasks in the presence or absence of 80 mM palmitic acid with or without 1.0 µM ibrutinib. The dissolved oxygen concentration (dO2) was initially set at 1 (left bar), and the relative dO2 after 48 hours is depicted in the middle and right bars.
Fig 2.
Fig 2.
Ibrutinib inhibits free fatty acid metabolism of CLL cells in vivo. After a median of 4 days (short exposure range: 2 to 7) and 147 days (long exposure range: 85 to 165) of treatment with ibrutinib, peripheral blood (PB) CLL cells were obtained from CLL patients prior to treatment and cultured in the presence or absence of 80 mM (A) palmitic acid, (B) oleic acid or (C) palmitic acid plus oleic acid. The dO2 was initially set at 1 (white bars), and the relative concentration of dO2 after 48 hours is depicted after short (middle bars) and long (right bars) durations of ibrutinib treatment. (D) Viability of CLL cells incubated with palmitic or oleic acid with or without ibrutinib. (E) Ibrutinib downregulates LPL’s mRNA levels. CLL cells were incubated with 0.5 μM ibrutinib for 48 hours. Cellular RNA was extracted and subjected to quantitative reverse transcription–polymerase chain reaction testing using primers directed to detect the STAT3-regulated genes Bcl2, Cyclin D1, MCL1, c-Myc, p21, RelA, STAT3 and LPL. The experiment was repeated using PB CLL cells from 3 different patients. The means and standard errors of the means are depicted as fold change (fold reduction in the genes’ mRNA levels). As shown, ibrutinib reduced mRNA levels of STAT3-_target genes, including LPL. (F) Ibrutinib downregulates STAT3, serine pSTAT3 and LPL levels in a time- and dose-dependent manner. Left panel: CLL cells were incubated without or with 0.25 μM or 0.5 μM ibrutinib for 24 hours. Western immunoblotting shows a dose-dependent decrease in levels of serine pSTAT3, STAT3 and LPL. For positive controls, we used 3T3 cells. Right panel: CLL cells were incubated with 0.5 μM ibrutinib and harvested at 4 time points (0 - 2h). Western immunoblotting shows a time-dependent decrease in serine pSTAT3 and STAT3 protein levels.
Fig 2.
Fig 2.
Ibrutinib inhibits free fatty acid metabolism of CLL cells in vivo. After a median of 4 days (short exposure range: 2 to 7) and 147 days (long exposure range: 85 to 165) of treatment with ibrutinib, peripheral blood (PB) CLL cells were obtained from CLL patients prior to treatment and cultured in the presence or absence of 80 mM (A) palmitic acid, (B) oleic acid or (C) palmitic acid plus oleic acid. The dO2 was initially set at 1 (white bars), and the relative concentration of dO2 after 48 hours is depicted after short (middle bars) and long (right bars) durations of ibrutinib treatment. (D) Viability of CLL cells incubated with palmitic or oleic acid with or without ibrutinib. (E) Ibrutinib downregulates LPL’s mRNA levels. CLL cells were incubated with 0.5 μM ibrutinib for 48 hours. Cellular RNA was extracted and subjected to quantitative reverse transcription–polymerase chain reaction testing using primers directed to detect the STAT3-regulated genes Bcl2, Cyclin D1, MCL1, c-Myc, p21, RelA, STAT3 and LPL. The experiment was repeated using PB CLL cells from 3 different patients. The means and standard errors of the means are depicted as fold change (fold reduction in the genes’ mRNA levels). As shown, ibrutinib reduced mRNA levels of STAT3-_target genes, including LPL. (F) Ibrutinib downregulates STAT3, serine pSTAT3 and LPL levels in a time- and dose-dependent manner. Left panel: CLL cells were incubated without or with 0.25 μM or 0.5 μM ibrutinib for 24 hours. Western immunoblotting shows a dose-dependent decrease in levels of serine pSTAT3, STAT3 and LPL. For positive controls, we used 3T3 cells. Right panel: CLL cells were incubated with 0.5 μM ibrutinib and harvested at 4 time points (0 - 2h). Western immunoblotting shows a time-dependent decrease in serine pSTAT3 and STAT3 protein levels.
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