Dihydroorotate dehydrogenase inhibition reveals metabolic vulnerability in chronic myeloid leukemia.

Mohammad Houshmand, Nicoletta Vitale, Francesca Orso, Alessandro Cignetti, Ivan Molineris, Valentina Gaidano, Stefano Sainas, Marta Giorgis, Donatella Boschi, Carmen Fava, Alice Passoni, Marta Gai, Massimo Geuna, Federica Sora, Alessandra Iurlo, Elisabetta Abruzzese, Massimo Breccia, Olga Mulas, Giovanni Caocci, Fausto Castagnetti, Daniela Taverna, Salvatore Oliviero, Fabrizio Pane, Marco Lucio Lolli, Paola Circosta, Giuseppe Saglio

Journal: Cell death & disease 2022;13(6):576

PMID: 35773274

Free Full Text on Nature Publishing Group View on PubMed

Abstract

The development of different generations of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has led to the high overall survival of chronic myeloid leukemia (CML) patients. However, there are CML patients who show resistance to TKI therapy and are prone to progress to more advanced phases of the disease. So, implementing an alternative approach for targeting TKIs insensitive cells would be of the essence. Dihydroorotate dehydrogenase (DHODH) is an enzyme in the de novo pyrimidine biosynthesis pathway that is located in the inner membrane of mitochondria. Here, we found that CML cells are vulnerable to DHODH inhibition mediated by Meds433, a new and potent DHODH inhibitor recently developed by our group. Meds433 significantly activates the apoptotic pathway and leads to the reduction of amino acids and induction of huge metabolic stress in CML CD34+ cells. Altogether, our study shows that DHODH inhibition is a promising approach for targeting CML stem/progenitor cells and may help more patients discontinue the therapy.

Address: Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.; Department of Medical Sciences, University of Turin, Turin, Italy.; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.; Department of Hematology and Cell Therapy, A.O. Ordine Mauriziano, Turin, Italy.; Department of Life Sciences and Systems Biology, University of Turin, Turin, Italy.; IIGM - Italian Institute for Genomic Medicine, c/o IRCCS, Candiolo, Italy.; Division of Hematology, A.O. SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.; Department of Drug Science and Technology, University of Turin, Turin, Italy.; Mass spectrometry Laboratory, Environmental Health Sciences Department, Institute for Pharmacological Research Mario Negri Institute IRCCS, Milan, Italy.; Laboratory of Immunopathology, Division of Pathology, A.O. Ordine Mauriziano, Turin, Italy.; Fondazione Policlinico Universitario A Gemelli-IRCCS, Istituto di Ematologia Università Cattolica Sacro Cuore, Rome, Italy.; Hematology Division, Foundation Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.; Hematology Unit, S. Eugenio Hospital, ASLRoma2, Rome, Italy.; Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.; Department of Medical Sciences and Public Health, University of Cagliari, Businco Hospital, Cagliari, Italy.; Institute of Hematology "L. and A. Seràgnoli", Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, "S. Orsola-Malpighi" Hospital, Bologna, Italy.; Department of Life Sciences and Systems Biology, University of Turin, Turin, Italy.; Department of Clinical Medicine and Surgery, Hematology Section, University of Naples "Federico II", Naples, Italy.; Department of Clinical and Biological Sciences, University of Turin, Turin, Italy. [email protected].; Department of Clinical and Biological Sciences, University of Turin, Turin, Italy. [email protected].

DOI: 10.1038/s41419-022-05028-9

Link outs

Free resources

Full Text Sources:

Medical:

https://medlineplus.gov/chronicmyeloidleukemia.htm...

Miscellaneous:

https://assays.cancer.gov/CPTAC-1776

Molecular Biology Databases:

https://data.niaid.nih.gov/resources?id=gse177485

MeSH Terms: Dihydroorotate Dehydrogenase, Drug Resistance, Neoplasm, Fusion Proteins, bcr-abl, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Protein Kinase Inhibitors