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Oncotarget. 2018 Jul 3;9(51):29665-29679. doi: 10.18632/oncotarget.25667. eCollection 2018 Jul 3.

KLF5 controls glutathione metabolism to suppress p190-BCR-ABL+ B-cell lymphoblastic leukemia.

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Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Department of Biochemistry and Molecular Genetics, University of Colorado Denver-Anschutz, Aurora, CO, USA.
Hoxworth Blood Center, University of Cincinnati, Cincinnati, OH, USA.
Department of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, Boston, MA, USA.
Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA, USA.
Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Immunobiology and Center for Systems Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.


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 Klf5∆/∆ 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.


GSTM1; KLF5; metabolome; philadelphia+; preB-lymphoblastic leukemia

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