Bone marrow stromal cells reduce low-dose cytarabine-induced differentiation of acute myeloid leukemia

Scientific paper - Original scientific paper

• Author: Tomislav Smoljo
• Author: Barbara Tomic
• Author: Hrvoje Lalić
• Author: Vilma Dembitz
• Author: Josip Batinić
• 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)

Low-dose cytarabine (LDAC) is a standard therapy for elderly acute myeloid leukemia (AML) patients unfit for intensive chemotherapy. While high doses of cytarabine induce cytotoxicity, the precise mechanism of action of LDAC in AML remains elusive. In vitro studies have demonstrated LDAC-induced differentiation; however, such differentiation is seldom observed in vivo. We hypothesize that this discrepancy may be attributed to the influence of bone marrow (BM) stromal cells on AML cells. Thus, this study aimed to investigate the impact of BM stromal cells on LDAC-induced differentiation of AML cell lines and primary samples. Our results demonstrate that the presence of MS-5 stromal cells prevented LDAC-induced cell cycle arrest, DNA damage signaling and differentiation of U937 and MOLM-13 cell lines. Although transcriptomic analysis revealed that the stroma reduces the expression of genes involved in cytokine signaling and oxidative stress, data obtained with pharmacological inhibitors and neutralizing antibodies did not support the role for CXCL12, TGF-β1 or reactive oxygen species. The presence of stromal cells reduces LDAC-induced differentiation in primary samples from AML-M4 and myelodysplastic syndrome/AML patients. In conclusion, our study demonstrates that BM stroma reduces differentiation of AML induced by LDAC. These findings provide insights into the limited occurrence of terminal differentiation observed in AML patients, and suggest a potential explanation for this observation.

• Keywords (english): acute myeloid leukemia; bone marrow stromal cells; cell cycle; cytarabine; differentiation
• Language: english
• Publication type: Scientific paper - Original scientific paper
• Publication status: Published
• Peer review: Peer review
• Publication version: Published version
• Journal title: Frontiers in Pharmacology
• Numbering: vol. 14, 1258151
• e-ISSN: 1663-9812
• DOI: https://doi.org/10.3389/fphar.2023.1258151
• URN:NBN: urn:nbn:hr:105:853860
• Publication: 2023-10-26
• Document URL: https://www.frontiersin.org/articles/10.3389/fphar.2023.1258151/full
• Type of resource: Text
• Access conditions: Open access
• Created on: 2024-04-12 11:07:27