2. Academic Validation
  3. Epigenetic-based differentiation therapy for Acute Myeloid Leukemia

Epigenetic-based differentiation therapy for Acute Myeloid Leukemia

  • Nat Commun. 2024 Jul 2;15(1):5570. doi: 10.1038/s41467-024-49784-y.
Edurne San José-Enériz # 1 2,  Naroa Gimenez-Camino # 1 2,  Obdulia Rabal 3,  Leire Garate 1 2,  Estibaliz Miranda 1 2,  Nahia Gómez-Echarte 1,  Fernando García 4,  Stella Charalampopoulou 5,  Elena Sáez 3,  Amaia Vilas-Zornoza 1,  Patxi San Martín-Uriz 1,  Luis V Valcárcel 1 2 6,  Naroa Barrena 6,  Diego Alignani 1 2,  Luis Esteban Tamariz-Amador 1 2 7,  Ana Pérez-Ruiz 8,  Sebastian Hilscher 9 10,  Mike Schutkowski 9 10,  Ana Alfonso-Pierola 1 2 7,  Nicolás Martinez-Calle 1 2 7,  María José Larrayoz 11,  Bruno Paiva 1 2,  María José Calasanz 11,  Javier Muñoz 12 13,  Marta Isasa 4,  José Ignacio Martin-Subero 2 5 14 15,  Antonio Pineda-Lucena 3,  Julen Oyarzabal 16,  Xabier Agirre 17 18,  Felipe Prósper 19 20 21
Affiliations

Affiliations

  • 1 Hemato-Oncology Program, Center for Applied Medical Research (CIMA), Universidad de Navarra, IDISNA, CCUN, Avenida Pío XII 55, 31008, Pamplona, Spain.
  • 2 Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029, Madrid, Spain.
  • 3 Small-Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), Universidad de Navarra, Avenida Pío XII 55, 31008, Pamplona, Spain.
  • 4 ProteoRed-ISCIII, Unidad de Proteómica, Centro Nacional de Investigaciones Oncológicas (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain.
  • 5 Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Casanova 143, 08036, Barcelona, Spain.
  • 6 TECNUN, Universidad de Navarra, Manuel de Lardizábal 13, 20018, San Sebastián, Spain.
  • 7 Departmento de Hematología, Clínica Universidad de Navarra, and CCUN, Universidad de Navarra, Avenida Pío XII 36, 31008, Pamplona, Spain.
  • 8 Biomedical Engineering Program, Center for Applied Medical Research (CIMA), Universidad de Navarra, IDISNA, Avenida Pío XII 55, 31008, Pamplona, Spain.
  • 9 Department of Enzymology, Charles Tanford Protein Center, Institute of Biochemistry and Biotechnology, Martin-Luther-University Halle-Wittenberg, 06120, Halle, Germany.
  • 10 Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, 06120, Halle, Germany.
  • 11 CIMA LAB Diagnostics, Universidad de Navarra, Avenida Pío XII 55, 31008, Pamplona, Spain.
  • 12 Biocruces Bizkaia Health Research Institute, Cruces Plaza, 48903, Barakaldo, Spain.
  • 13 Ikerbasque, Basque Foundation for Science, Plaza Euskadi 5, 48009, Bilbao, Spain.
  • 14 Departamento de Fundamentos Clínicos, Universitat de Barcelona, Casanova 143, 08036, Barcelona, Spain.
  • 15 Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig de Lluís Companys 23, 08010, Barcelona, Spain.
  • 16 Small-Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), Universidad de Navarra, Avenida Pío XII 55, 31008, Pamplona, Spain. julenoyarzabal@external.unav.es.
  • 17 Hemato-Oncology Program, Center for Applied Medical Research (CIMA), Universidad de Navarra, IDISNA, CCUN, Avenida Pío XII 55, 31008, Pamplona, Spain. xaguirre@unav.es.
  • 18 Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029, Madrid, Spain. xaguirre@unav.es.
  • 19 Hemato-Oncology Program, Center for Applied Medical Research (CIMA), Universidad de Navarra, IDISNA, CCUN, Avenida Pío XII 55, 31008, Pamplona, Spain. fprosper@unav.es.
  • 20 Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029, Madrid, Spain. fprosper@unav.es.
  • 21 Departmento de Hematología, Clínica Universidad de Navarra, and CCUN, Universidad de Navarra, Avenida Pío XII 36, 31008, Pamplona, Spain. fprosper@unav.es.
  • # Contributed equally.
PMID: 38956053 DOI: 10.1038/s41467-024-49784-y
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.

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