image: Figure 1: The RUNX1/AP-1 axis operates differently in different types of AML. Cytokine receptors are indicated in different colours with their ligand shown as coloured round shapes on the cell surface. Transcription factors such as JUN and FOS are indicated as elliptical shapes with the DNA binding domains depicted lines below the shape. Gene names are in italics. Asterisks depict phosphorylated proteins. FLT3i, RASi, VEGFi and IL-5i are inhibitors of the respective signalling pathways. RUNX/CBFβi and dnFOS inhibit RUNX1 and AP-1 DNA binding, respectively. The mutant DNA binding domain in dnFOS blocks JUN family members from binding and is shown as a red elliptical shape. Arrows indicate activation, inhibitory action is indicated by a red bar. (A) Interplay between signalling and the RUNX1/ AP-1 axis in FLT3-ITD AML. (B) Interplay between signalling and the RUNX1/AP-1 axis in t(8;21) AML. The RUNX1-ETO fusion protein consists of the RUNX1 DNA binding domain fused to the ETO (RUNX1T1) protein is indication by two shapes fused together.
Credit: 2024 Bonifer and Cockerill
“[...] drugs that target individual signalling pathways in AML often fail to stop proliferation malignant growth, due to the wide variety, redundancy and cross talk between multiple pathways regulating and differentiation.”
BUFFALO, NY- October 23, 2024 – A new editorial was published in Oncotarget's Volume 15 on October 11, 2024, entitled, “Gene regulatory network and signalling pathway rewiring: How blood cancer cells shift their shapes to evade drug treatment.”
As highlighted in the paper, Acute Myeloid Leukemia (AML) is a complex and diverse disease caused by multiple mutations in genes that regulate transcription and growth. These mutations lead to extensive rewiring of the gene regulatory network (GRN), which alters the identity of hematopoietic stem and progenitor cells, ultimately blocking normal myeloid differentiation. A key feature of AML is the presence of mutations in growth factor receptor and signaling genes, such as FLT3, KIT, and RAS. Notably, FLT3 is one of the most commonly mutated genes in AML, with around 25% of cases showing an internal tandem duplication (ITD) that causes the receptor to remain constantly active.
In their paper, researchers Constanze Bonifer and Peter N. Cockerill from the Institute of Cancer and Genomic Sciences at the University of Birmingham, UK, and the Murdoch Children’s Research Institute, Royal Children’s Hospital in Melbourne, Australia, discuss recent publications from their group addressing this issue through a multi-omics study. The authors investigated how gene regulatory networks (GRNs) in FLT3-ITD patients were rewired compared to normal cells and in response to FLT3 inhibitor treatment. Several key findings stood out, including: 1) Mapping of open chromatin regions revealed that patients initially responsive to FLT3 inhibition showed significant rewiring of their GRNs, forming new connections between transcription factors (TFs) and target genes, while non-responsive patients did not; 2) Chromatin immunoprecipitation (ChIP) experiments showed that drug treatment led to the loss of binding of RUNX1, the master regulator of hematopoiesis, and the MAP-Kinase (MAPK)-inducible TF AP-1; 3) Disruption of AP-1 binding via a dominant-negative version of the TF (dnFOS) also abolished RUNX1 binding at hundreds of sites, indicating that RUNX1 binding is AP-1 dependent; and 4) Inhibition of both AP-1 and RUNX1 led to a pronounced cell cycle block.
“In summary, drugs that target individual signalling pathways in AML often fail to stop proliferation malignant growth, due to the wide variety, redundancy and cross talk between multiple pathways regulating and differentiation.”
Continue reading: DOI: https://doi.org/10.18632/oncotarget.28662
Correspondence to: Constanze Bonifer - constanze.bonifer@mcri.edu.au
Keywords: cancer, acute myeloid leukemia, gene regulatory networks, aberrant growth factor signaling, transcription, RUNX1/AP-1 axis
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Journal
Oncotarget
Method of Research
Commentary/editorial
Subject of Research
Not applicable
Article Title
Gene regulatory network and signalling pathway rewiring: How blood cancer cells shift their shapes to evade drug treatment
Article Publication Date
11-Oct-2024
COI Statement
Authors have no conflicts of interest to declare.