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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Jul 10, 2018 |
| Title |
KLF5 controls glutathione metabolism to suppress p190-BCR-ABL+ B-cell lymphoblastic leukemia |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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 imatinib resistance 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 on 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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| Overall design |
p190-BCR-ABL+ Leukemic B-cell precursors mRNA profiles of WT and Klf5Δ/Δ mice were generated by deep sequencing, in triplicate, using Illumina HiSeq2500
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| Contributor(s) |
Zhang C, D'Alessandro A, Wellendorf A, Mohmoud F, Serrano-Lopez J, Perentesis J, Komurov K, Alexe G, Stegmaier K, Whitsett J, Grimes L, Cancelas J |
| Citation |
Cuiping Zhang, Angelo D'Alessandro, Ashley M. Wellendorf, Fatima Mohmoud, Juana Serrano-Lopez, John P. Perentesis, Kakajan Komurov, Gabriela Alexe, Kimberly Stegmaier, Jeffrey A. Whitsett, H. Leighton Grimes and Jose A. Cancelas. KLF5 controls glutathione metabolism to suppress p190-BCR-ABL+ B-cell lymphoblastic leukemia. Oncotarget 2018;9:29665-29679. doi:10.18632/oncotarget.25667
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| Submission date |
Jun 18, 2018 |
| Last update date |
Mar 21, 2019 |
| Contact name |
Jose Cancelas |
| Organization name |
Cincinnati Children's Hospital Medical Center
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| Street address |
3333 Burnet Ave, ML 7013
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| City |
Cincinnati |
| State/province |
OH |
| ZIP/Postal code |
45229 |
| Country |
USA |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA476502 |
| SRA |
SRP150711 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE115919_RAW.tar |
2.9 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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