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| Status |
Public on Dec 28, 2020 |
| Title |
CDK2-mediated TNFa Upregulation as a Mechanism of Cytotoxicity in Acute Leukemia |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Although inhibitors of the kinases CHK1, ATR and WEE1 are undergoing clinical testing, it remains unclear how these three classes of agents kill susceptible cells and whether they utilize the same cytotoxic mechanism. Here we observed that CHK1 inhibition induces apoptosis in a subset of acute leukemia cell lines, including TP53 null acute myeloid leukemia (AML) and BCR/ABL-positive acute lymphoid leukemia (ALL), in vitro and inhibits leukemic colony formation in clinical AML samples ex vivo. In further studies, CHK1 downregulation or CHK1 inhibitor treatment triggered signaling in sensitive human acute leukemia cell lines that involved CDK2 activation followed by AP1-dependent TNF transactivation, TNF production and engagement of a TNFR1- and BID-dependent apoptotic pathway. AML lines that were intrinsically CHK1 inhibitor resistant exhibited high CHK1 expression and were sensitized by CHK1 downregulation. Signaling through this same CDK2 AP1 TNF cytotoxic pathway was also initiated by ATR or WEE1 inhibitors in vitro and during CHK1 inhibitor treatment of AML xenografts in vivo. Collectively, these observations not only identify new contributors to antileukemic cell action of CHK1, ATR and WEE1 inhibitors, but also delineate a previously undescribed pathway leading from aberrant CDK2 activation to death ligand-induced killing that can potentially be exploited for acute leukemia treatment.
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| Overall design |
Compare RNAseq data from ML1 or U937 in different treatments to check significant mRNA change for potential TNFa transcription factors
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| |
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| Contributor(s) |
Kaufmann S, Li H |
| Citation(s) |
33414171 |
| |
| Submission date |
May 29, 2019 |
| Last update date |
Mar 29, 2021 |
| Contact name |
Hu Li |
| E-mail(s) |
li.hu@mayo.edu
|
| Organization name |
Mayo Clinic
|
| Department |
Molecular Pharmacology & Experimental Therapeutics
|
| Lab |
Systems Biology and Pharmacology
|
| Street address |
200 First Street, Gonda Building G19-408
|
| City |
Rochester |
| State/province |
MN |
| ZIP/Postal code |
55904 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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| Samples (15)
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| Relations |
| BioProject |
PRJNA545305 |
| SRA |
SRP199764 |
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