AI Article Synopsis
- Acute myeloid leukemia (AML) is a complex disease linked to various mutations, each creating its own gene regulatory network (GRN) with interacting transcription factors.
- Researchers tested the idea that important regulators for maintaining AML can be found in highly interconnected nodes of these GRNs, focusing on FLT3-ITD-mutated AML as their model.
- Their findings indicate that specific regulatory modules are essential for AML growth, and the transcription factor RUNX1 is critical, as its removal disrupts the GRN, leading to cell death.
Article Abstract
Acute myeloid leukemia (AML) is a heterogeneous disease caused by different mutations. Previously, we showed that each mutational subtype develops its specific gene regulatory network (GRN) with transcription factors interacting within multiple gene modules, many of which are transcription factor genes themselves. Here, we hypothesize that highly connected nodes within such networks comprise crucial regulators of AML maintenance. We test this hypothesis using FLT3-ITD-mutated AML as a model and conduct an shRNA drop-out screen informed by this analysis. We show that AML-specific GRNs predict crucial regulatory modules required for AML growth. Furthermore, our work shows that all modules are highly connected and regulate each other. The careful multi-omic analysis of the role of one (RUNX1) module by shRNA and chemical inhibition shows that this transcription factor and its target genes stabilize the GRN of FLT3-ITD+ AML and that its removal leads to GRN collapse and cell death.
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Source |
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10874628 | PMC |
| http://dx.doi.org/10.1016/j.celrep.2023.113568 | DOI Listing |
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