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

doi:10.1038/s41419-022-05028-9

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 CastagnettiDaniela Taverna, Salvatore Oliviero, Fabrizio Pane, Marco Lucio Lolli, Paola Circosta, Giuseppe Saglio

Risultato della ricerca: Contributo su rivista › Articolo in rivista › peer review

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.

Lingua originale	Inglese
Numero di articolo	576
Rivista	Cell Death and Disease
Volume	13
Numero di pubblicazione	6
DOI	https://doi.org/10.1038/s41419-022-05028-9
Stato di pubblicazione	Pubblicato - giu 2022
Pubblicato esternamente	Sì

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Houshmand, M., Vitale, N., Orso, F., Cignetti, A., Molineris, I., Gaidano, V., Sainas, S., Giorgis, M., Boschi, D., Fava, C., Passoni, A., Gai, M., Geuna, M., Sora, F., Iurlo, A., Abruzzese, E., Breccia, M., Mulas, O., Caocci, G., ... Saglio, G. (2022). Dihydroorotate dehydrogenase inhibition reveals metabolic vulnerability in chronic myeloid leukemia. Cell Death and Disease, 13(6), Articolo 576. https://doi.org/10.1038/s41419-022-05028-9

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title = "Dihydroorotate dehydrogenase inhibition reveals metabolic vulnerability in chronic myeloid leukemia",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = jun,

doi = "10.1038/s41419-022-05028-9",

language = "English",

volume = "13",

journal = "Cell Death and Disease",

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Houshmand, M, Vitale, N, Orso, F, Cignetti, A, Molineris, I, Gaidano, V, Sainas, S, Giorgis, M, Boschi, D, Fava, C, Passoni, A, Gai, M, Geuna, M, Sora, F, Iurlo, A, Abruzzese, E, Breccia, M, Mulas, O, Caocci, G, Castagnetti, F, Taverna, D, Oliviero, S, Pane, F, Lolli, ML, Circosta, P & Saglio, G 2022, 'Dihydroorotate dehydrogenase inhibition reveals metabolic vulnerability in chronic myeloid leukemia', Cell Death and Disease, vol. 13, n. 6, 576. https://doi.org/10.1038/s41419-022-05028-9

TY - JOUR

T1 - Dihydroorotate dehydrogenase inhibition reveals metabolic vulnerability in chronic myeloid leukemia

AU - Houshmand, Mohammad

AU - Vitale, Nicoletta

AU - Orso, Francesca

AU - Cignetti, Alessandro

AU - Molineris, Ivan

AU - Gaidano, Valentina

AU - Sainas, Stefano

AU - Giorgis, Marta

AU - Boschi, Donatella

AU - Fava, Carmen

AU - Passoni, Alice

AU - Gai, Marta

AU - Geuna, Massimo

AU - Sora, Federica

AU - Iurlo, Alessandra

AU - Abruzzese, Elisabetta

AU - Breccia, Massimo

AU - Mulas, Olga

AU - Caocci, Giovanni

AU - Castagnetti, Fausto

AU - Taverna, Daniela

AU - Oliviero, Salvatore

AU - Pane, Fabrizio

AU - Lolli, Marco Lucio

AU - Circosta, Paola

AU - Saglio, Giuseppe

PY - 2022/6

Y1 - 2022/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85133235930&partnerID=8YFLogxK

U2 - 10.1038/s41419-022-05028-9

DO - 10.1038/s41419-022-05028-9

M3 - Article

SN - 2041-4889

VL - 13

JO - Cell Death and Disease

JF - Cell Death and Disease

IS - 6

M1 - 576

ER -

Dihydroorotate dehydrogenase inhibition reveals metabolic vulnerability in chronic myeloid leukemia

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