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.

Dihydroorotate dehydrogenase inhibition reveals metabolic vulnerability in chronic myeloid leukemia

Houshmand, Mohammad
First
;
Vitale, Nicoletta;Orso, Francesca;Cignetti, Alessandro;Molineris, Ivan;Gaidano, Valentina;Sainas, Stefano;Giorgis, Marta;Boschi, Donatella;Fava, Carmen;Gai, Marta;Taverna, Daniela;Oliviero, Salvatore;Lolli, Marco Lucio;Circosta, Paola
;
Saglio, Giuseppe
2022-01-01

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.
13
6
576
588
https://www.nature.com/articles/s41419-022-05028-9
Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Humans; Protein Kinase Inhibitors; Dihydroorotate Dehydrogenase; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
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
File in questo prodotto:
File Dimensione Formato  
s41419-022-05028-9-1.pdf

Accesso riservato

Descrizione: Articolo
Tipo di file: PDF EDITORIALE
Dimensione 6.76 MB
Formato Adobe PDF
6.76 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1879145
Citazioni
  • ???jsp.display-item.citation.pmc??? 0
  • Scopus 0
  • ???jsp.display-item.citation.isi??? 0
social impact