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| Status |
Public on Mar 22, 2024 |
| Title |
Unveiling the signaling network of FLT3-ITD AML improves drug sensitivity prediction |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Currently, the identification of patient-specific therapies in cancer is mainly informed by personalized genomic analysis. In the setting of acute myeloid leukemia (AML), patient-drug treatment matching fails in a subset of patients harboring atypical internal tandem duplications (ITDs) in the tyrosine kinase domain of the FLT3 gene. To address this unmet medical need, here we develop a systems-based strategy that integrates multiparametric analysis of crucial signaling pathways, patient-specific genomic and transcriptomic data with a prior-knowledge signaling network using a Boolean-based formalism. By this approach, we derive personalized predictive models describing the signaling landscape of AML FLT3-ITD positive cell lines and patients. These models enable us to derive mechanistic insight into drug resistance mechanisms and suggest novel opportunities for combinatorial treatments. Interestingly, our analysis reveals that the JNK kinase pathway plays a crucial role in the tyrosine kinase inhibitor response of FLT3-ITD cells through cell cycle regulation. Finally, our work shows that patient-specific logic models have the potential to inform precision medicine approaches.
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| Overall design |
RNA was sequenced from peripheral blasts of 14 treatment naïve patients with de novo FLT3 ITD driven-AML diagnosis.
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| Contributor(s) |
Latini S, Venafra V, Massacci G, Bica V, Graziosi S, Pugliese GM, Iannuccelli M, Frioni F, Minnella G, Marra JD, Chiusolo P, Pepe G, Helmer-Citterich M, Mougiakakos D, Boettcher M, Fischer T, Perfetto L, Sacco F |
| Citation(s) |
38564252 |
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| Submission date |
Nov 10, 2023 |
| Last update date |
Apr 17, 2024 |
| Contact name |
Gerardo Pepe |
| E-mail(s) |
gerardo.pepe@uniroma2.it
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| Phone |
+39 06-72594316
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| Organization name |
Tor Vergara University
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| Street address |
via della ricerca scientifica
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| City |
Rome |
| ZIP/Postal code |
00133 |
| Country |
Italy |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (14)
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| Relations |
| BioProject |
PRJNA1038767 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE247483_raw_counts.tsv.gz |
359.9 Kb |
(ftp)(http) |
TSV |
SRA Run Selector |
| Raw data are available in SRA |
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