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| Status |
Public on Aug 09, 2024 |
| Title |
RAS-mutant AML LSCs originate from GMPs and drive clinical resistance to BH3 mimetics [RNA-Seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Cancer driver mutations often show distinct temporal acquisition patterns, but the biological basis for this, if any, remains unknown. RAS mutations occur invariably late in the course of acute myeloid leukemia (AML), upon progression or relapsed/refractory disease1-6. Here, by employing synthetic leukemogenesis in human cells, we first show that RAS mutations are obligatory late events that need to succeed earlier cooperating mutations. We provide the mechanistic explanation for this in a requirement for mutant RAS to specifically transform committed progenitors of the myelomonocytic lineage (granulocyte-monocyte progenitors, GMPs) harboring previously acquired driver mutations, revealing that advanced leukemic clones originate from a different cell type than more ancestral clones. Furthermore, we demonstrate that RAS-mutant leukemia stem cells (LSCs) give rise to monocytic disease, as frequently observed in patients with poor responses to treatment with the BCL2 inhibitor drug Venetoclax (VEN). We show that this is because RAS-mutant LSCs, in contrast to RAS-WT LSCs, have altered BCL2 family gene expression profiles and are resistant to VEN, driving clinical resistance and relapse with monocytic features. Our findings demonstrate that a specific genetic driver by imposing a specific LSC target cell restriction shapes the non-genetic cellular hierarchy of AML and critically impacts therapeutic outcomes in patients.
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| Overall design |
Synthetic leukemogenesis models in human iPSC-HSPCs and primary CB HSPCs
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| |
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| Contributor(s) |
Papapetrou E |
| Citation missing |
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| |
| Submission date |
Jan 17, 2024 |
| Last update date |
Aug 09, 2024 |
| Contact name |
BiNGS Core |
| E-mail(s) |
bings.analytics@gmail.com
|
| Organization name |
Icahn School of Medicine at Mount Sinai
|
| Street address |
1470 Madison Ave
|
| City |
New York |
| ZIP/Postal code |
10029 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (18)
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| This SubSeries is part of SuperSeries: |
| GSE253715 |
RAS-mutant AML LSCs originate from GMPs and drive clinical resistance to BH3 mimetics |
|
| Relations |
| BioProject |
PRJNA1065778 |
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