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Early changes in gene expression profiles in AML patients during induction chemotherapy
Örebro University, School of Medical Sciences. Örebro University Hospital. Division of Clinical Chemistry and Pharmacology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden; Department of Laboratory Medicine, School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.ORCID iD: 0000-0003-4450-0333
Division of Clinical Chemistry and Pharmacology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden.
Division of Clinical Chemistry and Pharmacology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden.
Division of Clinical Chemistry and Pharmacology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden; Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
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2022 (English)In: BMC Genomics, E-ISSN 1471-2164, Vol. 23, no 1, article id 752Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2022. Vol. 23, no 1, article id 752
Keywords [en]
AML, Gene expression, RNA sequencing, Time course analys
National Category
Hematology
Identifiers
URN: urn:nbn:se:oru:diva-102241DOI: 10.1186/s12864-022-08960-4ISI: 000883397100001PubMedID: 36376859Scopus ID: 2-s2.0-85141866722OAI: oai:DiVA.org:oru-102241DiVA, id: diva2:1711158
Funder
Linköpings universitetSwedish Cancer Society
Note

Funding agencies:

Lions research fund for noncommunicable diseases

Clas Groschinsky Memorial Fund

Available from: 2022-11-16 Created: 2022-11-16 Last updated: 2024-01-17Bibliographically approved

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Jakobsen Falk, Ingrid

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