At high levels, constitutively activated STAT3 induces apoptosis of chronic lymphocytic leukemia cells

Uri Rozovski, David M. Harris, Ping Li, Zhiming Liu, Ji Yuan Wu, Srdana Grgurevic, Stefan Faderl, Alessandra Ferrajoli, William G. Wierda, Matthew Martinez, Srdan Verstovsek, Michael J. Keating, Zeev Estrov

Research output: Contribution to journalArticlepeer-review

Abstract

In chronic lymphocytic leukemia (CLL), the increment in PBLs is slower than the expected increment calculated from the cells' proliferation rate, suggesting that cellular proliferation and apoptosis are concurrent. Exploring this phenomenon, we found overexpression of caspase-3, higher cleaved poly (ADP-ribose) polymerase levels (p < 0.007), and a higher apoptosis rate in cells from patients with high counts compared with cells from patients with low counts. Although we previously found that STAT3 protects CLL cells from apoptosis, STAT3 levels were significantly higher in cells from patients with high counts than in cells from patients with low counts. Furthermore, overexpression of STAT3 did not protect the cells. Rather, it upregulated caspase-3 and induced apoptosis. Remarkably, putative STAT3 binding sites were identified in the caspase-3 promoter, and a luciferase assay, chromatin immunoprecipitation, and an EMSA revealed that STAT3 activated caspase-3. However, caspase-3 levels increased only when STAT3 levels were sufficiently high. Using chromatin immunoprecipitation and EMSA, we found that STAT3 binds with low affinity to the caspase-3 promoter, suggesting that at high levels, STAT3 activates proapoptotic mechanisms and induces apoptosis in CLL cells.

Original languageEnglish
Pages (from-to)4400-4409
Number of pages10
JournalJournal of Immunology
Volume196
Issue number10
DOIs
StatePublished - 15 May 2016
Externally publishedYes

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