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Systems Biology for Drug Target Discovery in Acute Myeloid Leukemia.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2024 Apr 23; Vol. 25 (9). Date of Electronic Publication: 2024 Apr 23. - Publication Year :
- 2024
-
Abstract
- Combining new therapeutics with all- trans -retinoic acid (ATRA) could improve the efficiency of acute myeloid leukemia (AML) treatment. Modeling the process of ATRA-induced differentiation based on the transcriptomic profile of leukemic cells resulted in the identification of key targets that can be used to increase the therapeutic effect of ATRA. The genome-scale transcriptome analysis revealed the early molecular response to the ATRA treatment of HL-60 cells. In this study, we performed the transcriptomic profiling of HL-60, NB4, and K562 cells exposed to ATRA for 3-72 h. After treatment with ATRA for 3, 12, 24, and 72 h, we found 222, 391, 359, and 1032 differentially expressed genes (DEGs) in HL-60 cells, as well as 641, 1037, 1011, and 1499 DEGs in NB4 cells. We also found 538 and 119 DEGs in K562 cells treated with ATRA for 24 h and 72 h, respectively. Based on experimental transcriptomic data, we performed hierarchical modeling and determined cyclin-dependent kinase 6 (CDK6), tumor necrosis factor alpha (TNF-alpha), and transcriptional repressor CUX1 as the key regulators of the molecular response to the ATRA treatment in HL-60, NB4, and K562 cell lines, respectively. Mapping the data of TMT-based mass-spectrometric profiling on the modeling schemes, we determined CDK6 expression at the proteome level and its down-regulation at the transcriptome and proteome levels in cells treated with ATRA for 72 h. The combination of therapy with a CDK6 inhibitor (palbociclib) and ATRA (tretinoin) could be an alternative approach for the treatment of acute myeloid leukemia (AML).
- Subjects :
- Humans
HL-60 Cells
Gene Expression Profiling
K562 Cells
Drug Discovery methods
Transcriptome
Cell Line, Tumor
Cyclin-Dependent Kinase 6 metabolism
Cyclin-Dependent Kinase 6 genetics
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Gene Expression Regulation, Leukemic drug effects
Tumor Necrosis Factor-alpha metabolism
Leukemia, Myeloid, Acute drug therapy
Leukemia, Myeloid, Acute genetics
Leukemia, Myeloid, Acute metabolism
Leukemia, Myeloid, Acute pathology
Tretinoin pharmacology
Systems Biology methods
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 25
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 38731835
- Full Text :
- https://doi.org/10.3390/ijms25094618