Bone marrow stromal cells enhance differentiation of acute myeloid leukemia induced by pyrimidine synthesis inhibitors

Scientific paper - Original scientific paper

• Author: Tomislav Smoljo
• Author: Hrvoje Lalić
• Author: Vilma Dembitz
• Author: Barbara Tomić
• Author: Josip Batinić
• Author: Radovan Vrhovac
• Author: Antonio Bedalov
• Author: Dora Višnjić
• Author's institution: University of Zagreb; School of Medicine; (Croatian Institiute for Brain Research)
• Author's institution: University of Zagreb; School of Medicine; (Department of Physiology and Immunology)
• Author's institution: University of Zagreb; School of Medicine; (Department of Internal Medicine)
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Basic Medical Sciences; Human Physiology
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences; Internal Medicine

Abstract (english)

Acute myeloid leukemia (AML) is a heterogeneous group of hematological malignancies characterized by differentiation arrest, high relapse rates, and poor survival. The bone marrow (BM) microenvironment is recognized as a critical mediator of drug resistance and a primary site responsible for AML relapse. Our previous study reported that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr) induces AML cell differentiation by inhibiting pyrimidine synthesis and activating Checkpoint kinase 1. Although the protective effect of BM stroma on leukemia cells in response to cytotoxic drugs is well-documented, its effect on AML differentiation remains less explored. In this study, we investigated the impact of stromal cell lines and primary mesenchymal stromal cells (MSCs) on AML cell line differentiation triggered by AICAr and brequinar, a known dihydroorotate dehydrogenase (DHODH) inhibitor. Our findings indicate that the mouse MS-5 stromal cell line, known for its cytoprotective effects, does not inhibit AML cell differentiation induced by pyrimidine synthesis inhibitors. Interestingly, AICAr caused morphological changes and growth arrest in MS-5 stromal cells via an AMP-activated protein kinase (AMPK)-dependent pathway. Human stromal cell lines HS-5 and HS-27, as well as primary MSCs isolated from patient bone marrow, were superior in promoting AML differentiation compared with mouse cells in response to AICAr and brequinar, with the inhibitors not significantly affecting the stromal cells themselves. In conclusion, our study highlights the supportive role of human BM MSCs in enhancing the differentiation effects of pyrimidine synthesis inhibitors on AML cells, suggesting that AML treatment strategies focusing on differentiation rather than cell killing may be successful in clinical settings.
NEW & NOTEWORTHY
This study is the first to demonstrate that human stromal cell lines and primary mesenchymal stromal cells from patients enhance the in vitro differentiation of acute myeloid leukemia (AML) cells induced by pyrimidine synthesis inhibitors, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr), and brequinar. Furthermore, this is the first report to show that AICAr affects mouse bone marrow stromal cells by activating AMP-activated protein kinase (AMPK) and that human stromal cells are superior to mouse cells for testing the effects of drugs on AML differentiation.

• Keywords (english): AMP-Activated Protein Kinases / metabolism; Aminoimidazole Carboxamide / analogs & derivatives; Aminoimidazole Carboxamide / pharmacology; Animals; Biphenyl Compounds; Bone Marrow Cells / drug effects; Bone Marrow Cells / metabolism; Bone Marrow Cells / pathology; Cell Differentiation / drug effects; Cell Line, Tumor; Dihydroorotate Dehydrogenase; Humans; Leukemia, Myeloid, Acute / drug therapy; Leukemia, Myeloid, Acute / metabolism; Leukemia, Myeloid, Acute / pathology; Mesenchymal Stem Cells / drug effects; Mesenchymal Stem Cells / metabolism; Mesenchymal Stem Cells / pathology; Mice; Pyrimidines / pharmacology; Quinaldines; Ribonucleotides / pharmacology
• Language: english
• Publication type: Scientific paper - Original scientific paper
• Publication status: Published
• Peer review: Peer review
• Publication version: Published version
• Journal title: American Journal of Physiology-Cell Physiology
• Numbering: vol. 327, no. 5, pp. C1202-C1218
• p-ISSN: 0363-6143
• e-ISSN: 1522-1563
• DOI: https://doi.org/10.1152/ajpcell.00413.2024
• URN:NBN: urn:nbn:hr:105:030855
• Publication: 2024-11-01
• Document URL: https://journals.physiology.org/doi/10.1152/ajpcell.00413.2024
• Type of resource: Text
• Access conditions: Open access
• Created on: 2025-03-20 09:13:41