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

• DOI: 10.1152/ajpcell.00413.2024
• Publication Date: 2024-09-16T08:01:13Z
• Authors: Tomislav Smoljo; Hrvoje Lalic; Vilma Dembitz; Barbara Tomic; Josip Batinic; Radovan Vrhovac; Antonio Bedalov; Dora Visnjic
• Keywords: 0301 basic medicine; Aminoimidazole Carboxamide / analogs & derivatives; Dihydroorotate Dehydrogenase; Bone Marrow Cells; Quinaldines; AMP-Activated Protein Kinases; Cell Differentiation / drug effects; Bone Marrow Cells / pathology; Mice; 03 medical and health sciences; Aminoimidazole Carboxamide / pharmacology; Leukemia, Myeloid, Acute / pathology; Mesenchymal Stem Cells / drug effects; Cell Line, Tumor; Bone Marrow Cells / drug effects; Humans; Animals; AMP-Activated Protein Kinases / metabolism; Pyrimidines / pharmacology; Biphenyl Compounds; Mesenchymal Stem Cells / pathology; Bone Marrow Cells / metabolism; Mesenchymal Stem Cells; Cell Differentiation; Ribonucleotides; Aminoimidazole Carboxamide; Mesenchymal Stem Cells / metabolism; Leukemia, Myeloid, Acute; Pyrimidines; Leukemia, Myeloid, Acute / metabolism; Ribonucleotides / pharmacology; Leukemia, Myeloid, Acute / drug therapy; Research Article

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 recognized as critical mediator drug resistance primary site responsible for AML relapse. Our previous study reported that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr) induces cell inhibiting pyrimidine synthesis activating Checkpoint kinase 1. Although the protective effect BM stroma on cells in response to cytotoxic drugs well-documented, its remains less explored. In this study, we investigated impact stromal lines mesenchymal (MSCs) line triggered AICAr brequinar, known dihydroorotate dehydrogenase (DHODH) inhibitor. findings indicate mouse MS-5 line, cytoprotective effects, does not inhibit induced inhibitors. Interestingly, caused morphological changes growth arrest via an AMP-activated protein (AMPK)-dependent pathway. Human HS-5 HS-27, well MSCs isolated from patient marrow, were superior promoting compared with inhibitors significantly affecting themselves. conclusion, our highlights supportive role human enhancing effects cells, suggesting treatment strategies focusing rather than killing may be successful clinical settings.