Dihydroorotate dehydrogenase inhibition reveals metabolic vulnerability in chronic myeloid leukemia

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....

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Published in:Cell death & disease 2022-06, Vol.13 (6), p.576-13, Article 576
Main Authors: Houshmand, Mohammad, Vitale, Nicoletta, Orso, Francesca, Cignetti, Alessandro, Molineris, Ivan, Gaidano, Valentina, Sainas, Stefano, Giorgis, Marta, Boschi, Donatella, Fava, Carmen, Passoni, Alice, Gai, Marta, Geuna, Massimo, Sora, Federica, Iurlo, Alessandra, Abruzzese, Elisabetta, Breccia, Massimo, Mulas, Olga, Caocci, Giovanni, Castagnetti, Fausto, Taverna, Daniela, Oliviero, Salvatore, Pane, Fabrizio, Lolli, Marco Lucio, Circosta, Paola, Saglio, Giuseppe
Format: Article
Language:English
Subjects:
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Antibodies
Apoptosis
Biochemistry
Biomedical and Life Sciences
CD34 antigen
Cell Biology
Cell Culture
Chronic myeloid leukemia
Dehydrogenases
Dihydroorotate Dehydrogenase
Drug Resistance, Neoplasm
Fusion Proteins, bcr-abl - metabolism
Humans
Immunology
Leukemia
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism
Life Sciences
Metabolism
Mitochondria
Myeloid leukemia
Progenitor cells
Protein Kinase Inhibitors - pharmacology
Protein-tyrosine kinase
Stem cells
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Summary: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.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-022-05028-9