KLF5 controls glutathione metabolism to suppress p190-BCR-ABL+ B-cell lymphoblastic leukemia
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Cuiping Zhang1, Angelo D'Alessandro2, Ashley M. Wellendorf1, Fatima Mohmoud3, Juana Serrano-Lopez1, John P. Perentesis4, Kakajan Komurov1, Gabriela Alexe5,6, Kimberly Stegmaier5,6, Jeffrey A. Whitsett7, H. Leighton Grimes8 and Jose A. Cancelas1,3
1Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
2Department of Biochemistry and Molecular Genetics, University of Colorado Denver-Anschutz, Aurora, CO, USA
3Hoxworth Blood Center, University of Cincinnati, Cincinnati, OH, USA
4Department of Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
5Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, Boston, MA, USA
6Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA, USA
7Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
8Immunobiology and Center for Systems Immunology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
Jose A. Cancelas, email: Jose.Cancelas@uc.edu
Keywords: preB-lymphoblastic leukemia; philadelphia+; KLF5; GSTM1; metabolome
Received: October 05, 2017 Accepted: June 06, 2018 Published: July 03, 2018
High-risk B-cell acute lymphoblastic leukemia (B-ALL) remains a therapeutic challenge despite advances in the use of tyrosine kinase inhibitors and chimeric-antigen-receptor engineered T cells. Lymphoblastic-leukemia precursors are highly sensitive to oxidative stress. KLF5 is a member of the Krüppel-like family of transcription factors. KLF5 expression is repressed in B-ALL, including BCR-ABL1+ B-ALL. Here, we demonstrate that forced expression of KLF5 in B-ALL cells bypasses the imatinib resistance which is not associated with mutations of BCR-ABL. Expression of Klf5 impaired leukemogenic activity of BCR-ABL1+ B-cell precursors in vitro and in vivo. The complete genetic loss of Klf5 reduced oxidative stress, increased regeneration of reduced glutathione and decreased apoptosis of leukemic precursors. Klf5 regulation of glutathione levels was mediated by its regulation of glutathione-S-transferase Mu 1 (Gstm1), an important regulator of glutathione-mediated detoxification and protein glutathionylation. Expression of Klf5 or the direct Klf5 target gene Gstm1 inhibited clonogenic activity of Klf5Δ/Δ leukemic B-cell precursors and unveiled a Klf5-dependent regulatory loop in glutamine-dependent glutathione metabolism. In summary, we describe a novel mechanism of Klf5 B-ALL suppressor activity through its direct role on the metabolism of antioxidant glutathione levels, a crucial positive regulator of leukemic precursor survival.
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