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| Status |
Public on Oct 25, 2022 |
| Title |
DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression (RNA-Seq) |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Chronic myeloproliferative neoplasms (MPNs) exhibit a propensity for transformation to secondary acute myeloid leukemia (sAML), for which the underlying mechanisms remain poorly understood, resulting in limited treatment options and dismal clinical outcomes. Here, we performed bulk transcriptome profiling accompanied by single cell RNA-sequencing on CD34+ stem/progenitor cells from serial patient samples obtained at the chronic MPN and sAML phases, identifying aberrantly increased expression of dual-specificity phosphatase 6 (DUSP6) underlying disease transformation. Genetic and pharmacologic targeting of DUSP6 led to inhibition of S6 and JAK/STAT signaling, resulting in potent suppression of cell proliferation, while also reducing inflammatory cytokine production in primary samples. Furthermore, ectopic DUSP6 expression augmented proliferation and mediated JAK2 inhibitor resistance, while DUSP6 inhibition reduced colony-forming potential of JAK2 inhibitor-persistent patient cells. Mechanistically, DUSP6 perturbation dampened S6 signaling via inhibition of RSK1, which we identified as a second indispensable candidate associated with poor clinical outcome. Ectopic expression of DUSP6 in patient-derived xenograft (PDX) models exacerbated disease severity and led to early lethality, whereas DUSP6 knockdown suppressed leukemic engraftment. Finally, pharmacological inhibition of DUSP6 potently and specifically suppressed disease development across Jak2 V617F and MPL W515L MPN mouse models, as well as sAML PDXs, without inducing toxicity in healthy controls. These findings underscore DUSP6 in driving disease transformation and therapeutic resistance, and highlight the DUSP6-RSK1 axis as a novel, druggable pathway in myeloid malignancies.
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| Overall design |
mRNA profiling of HEL cells treated with BCI, BI-D1870, or combination, and HEL JAK2 inhibitor persistent cells
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| Web link |
https://www.nature.com/articles/s43018-022-00486-8
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| Contributor(s) |
Kong T, Oh ST |
| Citation(s) |
36581736 |
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| Submission date |
Dec 09, 2021 |
| Last update date |
Feb 11, 2023 |
| Contact name |
Tim Kong |
| E-mail(s) |
timkong@wustl.edu
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| Organization name |
Washington University School of Medicine
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| Street address |
CSRB 8838
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| City |
St. Louis |
| State/province |
MO |
| ZIP/Postal code |
63110 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (20)
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| This SubSeries is part of SuperSeries: |
| GSE214361 |
DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression |
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| Relations |
| BioProject |
PRJNA787454 |
| SRA |
SRP349960 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE190517_HEL_BCItreatment_raw_counts.tsv.gz |
1.7 Mb |
(ftp)(http) |
TSV |
| GSE190517_HEL_BID1870treatment_raw_counts.tsv.gz |
1.6 Mb |
(ftp)(http) |
TSV |
| GSE190517_HEL_persistent_raw_counts.tsv.gz |
1016.9 Kb |
(ftp)(http) |
TSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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