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| Status |
Public on Dec 31, 2019 |
| Title |
Glucocorticoids paradoxically facilitate steroid resistance in subsets of T-cell acute lymphoblastic leukemias and normal thymocytes |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Glucocorticoids (GCs) are a central component of therapy for patients with T-cell acute lymphoblastic leukemia (T-ALL) and while resistance to GCs is a strong negative prognostic indicator in T-ALL, mechanisms of GC resistance remain poorly understood. Using diagnostic samples from patients enrolled on the frontline Children’s Oncology Group (COG) T-ALL clinical trial AALL1231, we demonstrate that one-third of primary T-ALLs are resistant to GCs when cultured in the presence of interleukin-7 (IL7), a cytokine that is critical for normal T-cell function and that plays a well-established role in leukemogenesis. We demonstrate that in these T-ALLs and in distinct populations of normal developing thymocytes, GCs paradoxically induce their own resistance by promoting upregulation of IL7 receptor (IL7R) expression. In the presence of IL7, this augments downstream signal transduction resulting in increased STAT5 transcriptional output, which leads to upregulation of the pro-survival protein BCL-2. Taken together, these data demonstrate that IL7 mediates an intrinsic and physiologic mechanism of GC resistance in normal thymocyte development that is retained during leukemogenesis in a subset of T-ALLs and is reversible with targeted inhibition of the IL7R/JAK/STAT5/BCL-2 axis.
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| Overall design |
Transcriptomes of primary human T-cell acute lymphoblastic leukemias were generated by extracting RNA from primary bone marrow specimens and sequenced using Illumina-based methods.
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| Contributor(s) |
Meyer L, Huang B, Shannon K, Teachey D, Hermiston M |
| Citation(s) |
31687977 |
| |
| Submission date |
Sep 20, 2019 |
| Last update date |
Apr 01, 2020 |
| Contact name |
Benjamin Huang |
| Organization name |
University of California San Francisco
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| Street address |
1450 3rd Street
|
| City |
San Francisco |
| State/province |
CA |
| ZIP/Postal code |
94158 |
| Country |
USA |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (75)
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| Relations |
| BioProject |
PRJNA572580 |
| SRA |
SRP222752 |
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