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Published on: June 6, 2025
Early changes in gene expression profiles in AML patients during induction chemotherapy
Ingrid Jakobsen1,2, Max Sundkvist1, Niclas Björn1
1Division of Clinical Chemistry and Pharmacology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden.
Background:
Elucidation of the genetic mechanisms underlying treatment response to standard induction chemotherapy in AML patients is warranted, in order to aid in risk-adapted treatment decisions as novel treatments are emerging. In this pilot study, we explored the treatment-induced expression patterns in a small cohort of AML patients by analyzing differential gene expression (DGE) over the first 2 days of induction chemotherapy.
Methods:
Blood samples were collected from ten AML patients at baseline (before treatment initiation) and during the first 2 days of treatment (Day 1; approximately 24 h, and Day 2; approximately 48 h after treatment initiation, respectively) and RNA was extracted for subsequent RNA sequencing. DGE between time points were assessed by pairwise analysis using the R package edgeR version 3.18.1 in all patients as well as in relation to treatment response (complete remission, CR, vs non-complete remission, nCR). Ingenuity Pathway Analysis (Qiagen) software was used for pathway analysis and visualization.
Results:
After initial data quality control, two patients were excluded from further analysis, resulting in a final cohort of eight patients with data from all three timepoints. DGE analysis demonstrated activation of pathways with genes directly or indirectly associated with NF-κB signaling. Significant activation of the NF-κB pathway was seen in 50% of the patients 2 days after treatment start, while iNOS pathway effects could be identified already after 1 day. nCR patients displayed activation of pathways associated with cell cycle progression, oncogenesis and anti-apoptotic behavior, including the STAT3 pathway and Salvage pathways of pyrimidine ribonucleotides. Notably, a significant induction of cytidine deaminase, an enzyme responsible for the deamination of Ara-C, could be observed between baseline and Day 2 in the nCR patients but not in patients achieving CR.
Conclusions:
In conclusion, we show that time-course analysis of gene expression represents a feasible approach to identify relevant pathways affected by standard induction chemotherapy in AML patients. This poses as a potential method for elucidating new drug targets and biomarkers for categorizing disease aggressiveness and evaluating treatment response. However, more studies on larger cohorts are warranted to elucidate the transcriptional basis for drug response.
Insights
This study reveals that gene expression changes within the first two days of acute myeloid leukemia (AML) chemotherapy can predict treatment response. Early activation of NF-κB signaling and specific gene pathways in non-remission patients highlight potential biomarkers.
Area of Science:
- Genomics and Molecular Biology
- Hematology and Oncology
- Pharmacogenomics
Background:
- Understanding genetic factors influencing acute myeloid leukemia (AML) treatment response is crucial for personalized medicine.
- Emerging novel therapies necessitate better risk-adapted treatment strategies for AML patients.
- This pilot study investigates gene expression patterns during early induction chemotherapy in AML.
Purpose of the Study:
- To explore treatment-induced gene expression patterns in AML patients during the initial days of induction chemotherapy.
- To identify potential gene expression biomarkers associated with treatment response (complete remission vs. non-complete remission).
- To analyze differential gene expression (DGE) over time to understand chemotherapy's molecular effects.
Main Methods:
- Collected blood samples from ten AML patients at baseline, Day 1, and Day 2 of induction chemotherapy.
- Performed RNA sequencing to analyze differential gene expression (DGE) between time points.
- Utilized R package edgeR for DGE analysis and Ingenuity Pathway Analysis for pathway identification.
Main Results:
- Differential gene expression analysis revealed activation of NF-κB signaling pathways in 50% of patients by Day 2.
- Non-complete remission (nCR) patients showed activation of cell cycle, oncogenesis, and anti-apoptotic pathways, including STAT3.
- A significant induction of cytidine deaminase was observed in nCR patients, an enzyme linked to Ara-C deamination.
Conclusions:
- Time-course gene expression analysis is a feasible method to identify chemotherapy-affected pathways in AML.
- This approach can potentially uncover new drug targets and biomarkers for disease aggressiveness and treatment response.
- Larger cohort studies are required to fully elucidate the transcriptional basis of drug response in AML.
