Epigenetic-based differentiation therapy for Acute Myeloid Leukemia

Edurne San José-Enériz, Naroa Gimenez-Camino, Obdulia Rabal, Leire Garate, Estibaliz Miranda, Nahia Gómez-Echarte, Fernando García, Stella Charalampopoulou, Elena Sáez, Amaia Vilas-Zornoza, Patxi San Martín-Uriz, Luis V. Valcárcel, Naroa Barrena, Diego Alignani, Luis Esteban Tamariz-Amador, Ana Pérez-Ruiz, Sebastian Hilscher, Mike Schutkowski, Ana Alfonso-Pierola, Nicolás Martinez-Calle, María José Larrayoz, Bruno Paiva, María José Calasanz, Javier Muñoz, Marta Isasa, José Ignacio Martin-Subero, Antonio Pineda-Lucena, Julen Oyarzabal (), Xabier Agirre () and Felipe Prósper ()
Additional contact information
Edurne San José-Enériz: Universidad de Navarra, IDISNA, CCUN
Naroa Gimenez-Camino: Universidad de Navarra, IDISNA, CCUN
Obdulia Rabal: Universidad de Navarra
Leire Garate: Universidad de Navarra, IDISNA, CCUN
Estibaliz Miranda: Universidad de Navarra, IDISNA, CCUN
Nahia Gómez-Echarte: Universidad de Navarra, IDISNA, CCUN
Fernando García: Unidad de Proteómica, Centro Nacional de Investigaciones Oncológicas (CNIO)
Stella Charalampopoulou: Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS)
Elena Sáez: Universidad de Navarra
Amaia Vilas-Zornoza: Universidad de Navarra, IDISNA, CCUN
Patxi San Martín-Uriz: Universidad de Navarra, IDISNA, CCUN
Luis V. Valcárcel: Universidad de Navarra, IDISNA, CCUN
Naroa Barrena: Universidad de Navarra
Diego Alignani: Universidad de Navarra, IDISNA, CCUN
Luis Esteban Tamariz-Amador: Universidad de Navarra, IDISNA, CCUN
Ana Pérez-Ruiz: Universidad de Navarra, IDISNA
Sebastian Hilscher: Martin-Luther-University Halle-Wittenberg
Mike Schutkowski: Martin-Luther-University Halle-Wittenberg
Ana Alfonso-Pierola: Universidad de Navarra, IDISNA, CCUN
Nicolás Martinez-Calle: Universidad de Navarra, IDISNA, CCUN
María José Larrayoz: Universidad de Navarra
Bruno Paiva: Universidad de Navarra, IDISNA, CCUN
María José Calasanz: Universidad de Navarra
Javier Muñoz: Biocruces Bizkaia Health Research Institute
Marta Isasa: Unidad de Proteómica, Centro Nacional de Investigaciones Oncológicas (CNIO)
José Ignacio Martin-Subero: Centro de Investigación Biomédica en Red Cáncer (CIBERONC)
Antonio Pineda-Lucena: Universidad de Navarra
Julen Oyarzabal: Universidad de Navarra
Xabier Agirre: Universidad de Navarra, IDISNA, CCUN
Felipe Prósper: Universidad de Navarra, IDISNA, CCUN

Nature Communications, 2024, vol. 15, issue 1, 1-23

Abstract: Abstract Despite the development of novel therapies for acute myeloid leukemia, outcomes remain poor for most patients, and therapeutic improvements are an urgent unmet need. Although treatment regimens promoting differentiation have succeeded in the treatment of acute promyelocytic leukemia, their role in other acute myeloid leukemia subtypes needs to be explored. Here we identify and characterize two lysine deacetylase inhibitors, CM-444 and CM-1758, exhibiting the capacity to promote myeloid differentiation in all acute myeloid leukemia subtypes at low non-cytotoxic doses, unlike other commercial histone deacetylase inhibitors. Analyzing the acetylome after CM-444 and CM-1758 treatment reveals modulation of non-histone proteins involved in the enhancer–promoter chromatin regulatory complex, including bromodomain proteins. This acetylation is essential for enhancing the expression of key transcription factors directly involved in the differentiation therapy induced by CM-444/CM-1758 in acute myeloid leukemia. In summary, these compounds may represent effective differentiation-based therapeutic agents across acute myeloid leukemia subtypes with a potential mechanism for the treatment of acute myeloid leukemia.

Date: 2024
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DOI: 10.1038/s41467-024-49784-y

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