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| Status |
Public on Mar 14, 2021 |
| Title |
Acute myeloid leukemia cells resist chemotherapy through a transient senescence-like state [PDX] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
In acute myeloid leukemias (AML), chemotherapy is frequently followed by disease relapse, yet the mechanism by which AML reemerges is not fully understood. We hypothesized that chemotherapy induces senescence-like dormancy that facilitates survival to genotoxic exposure, allowing AML cells to endure treatment in a transiently dormant state while retaining potential for leukemic repopulation. Here, we show that primary AML cells exhibit hallmark senescence features following treatment with cytarabine (AraC), including growth arrest, increased cellular granularity, senescence-associated-β-galactosidase (SA-β-gal) activity, and senescence-associated transcriptomic alterations. Induction of AraC-induced premature senescence was regulated by the ATR kinase activity and mediated stress-survival. High-throughput single cell RNA (scRNA)-seq analysis of primary AML cells ex vivo and in vivo following chemotherapy suggest active transcriptional programming towards senescent-like dormancy instead of enrichment for leukemia stem cells (LSCs). scRNA-seq of sorted AraC-induced premature senescent AML cells demonstrated a heterogenous population including a fraction of cells with simultaneous expression of dormancy- and senescence-associated gene signatures. Xenotransplantation of AraC-induced premature senescent AML cells into mice demonstrated that senescent-like AML cells maintain leukemia-repopulating potential. Altogether, we propose a mechanism of AML relapse whereby AML cells tolerate chemotherapy via acquisition of a transient senescent-like state.
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| |
|
| Overall design |
Gene expression in AraC treated AML ex vivo culture, primary xenografts
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| |
|
| Contributor(s) |
Cihangir D, Teater M, Melnick AM |
| Citation(s) |
33500244 |
| |
| Submission date |
Mar 06, 2020 |
| Last update date |
Mar 14, 2021 |
| Contact name |
Matt Teater |
| E-mail(s) |
mrt2001@med.cornell.edu
|
| Organization name |
Weill Cornell Medical College
|
| Street address |
445 E 69th St
|
| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10021 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
|
| Samples (15)
|
|
| This SubSeries is part of SuperSeries: |
| GSE146544 |
Acute myeloid leukemia cells resist chemotherapy through a transient senescence-like state |
|
| Relations |
| BioProject |
PRJNA610898 |
| SRA |
SRP251927 |
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