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Epigenetic-based differentiation therapy for Acute Myeloid Leukemia

Author

Listed:
  • Edurne San José-Enériz

    (Universidad de Navarra, IDISNA, CCUN
    Centro de Investigación Biomédica en Red Cáncer (CIBERONC))

  • Naroa Gimenez-Camino

    (Universidad de Navarra, IDISNA, CCUN
    Centro de Investigación Biomédica en Red Cáncer (CIBERONC))

  • Obdulia Rabal

    (Universidad de Navarra)

  • Leire Garate

    (Universidad de Navarra, IDISNA, CCUN
    Centro de Investigación Biomédica en Red Cáncer (CIBERONC))

  • Estibaliz Miranda

    (Universidad de Navarra, IDISNA, CCUN
    Centro de Investigación Biomédica en Red Cáncer (CIBERONC))

  • 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
    Centro de Investigación Biomédica en Red Cáncer (CIBERONC)
    Universidad de Navarra)

  • Naroa Barrena

    (Universidad de Navarra)

  • Diego Alignani

    (Universidad de Navarra, IDISNA, CCUN
    Centro de Investigación Biomédica en Red Cáncer (CIBERONC))

  • Luis Esteban Tamariz-Amador

    (Universidad de Navarra, IDISNA, CCUN
    Centro de Investigación Biomédica en Red Cáncer (CIBERONC)
    Clínica Universidad de Navarra, and CCUN, Universidad de Navarra)

  • Ana Pérez-Ruiz

    (Universidad de Navarra, IDISNA)

  • Sebastian Hilscher

    (Martin-Luther-University Halle-Wittenberg
    Martin-Luther-University Halle-Wittenberg)

  • Mike Schutkowski

    (Martin-Luther-University Halle-Wittenberg
    Martin-Luther-University Halle-Wittenberg)

  • Ana Alfonso-Pierola

    (Universidad de Navarra, IDISNA, CCUN
    Centro de Investigación Biomédica en Red Cáncer (CIBERONC)
    Clínica Universidad de Navarra, and CCUN, Universidad de Navarra)

  • Nicolás Martinez-Calle

    (Universidad de Navarra, IDISNA, CCUN
    Centro de Investigación Biomédica en Red Cáncer (CIBERONC)
    Clínica Universidad de Navarra, and CCUN, Universidad de Navarra)

  • María José Larrayoz

    (Universidad de Navarra)

  • Bruno Paiva

    (Universidad de Navarra, IDISNA, CCUN
    Centro de Investigación Biomédica en Red Cáncer (CIBERONC))

  • María José Calasanz

    (Universidad de Navarra)

  • Javier Muñoz

    (Biocruces Bizkaia Health Research Institute
    Basque Foundation for Science)

  • Marta Isasa

    (Unidad de Proteómica, Centro Nacional de Investigaciones Oncológicas (CNIO))

  • José Ignacio Martin-Subero

    (Centro de Investigación Biomédica en Red Cáncer (CIBERONC)
    Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS)
    Universitat de Barcelona
    Institució Catalana de Recerca i Estudis Avançats (ICREA))

  • Antonio Pineda-Lucena

    (Universidad de Navarra)

  • Julen Oyarzabal

    (Universidad de Navarra)

  • Xabier Agirre

    (Universidad de Navarra, IDISNA, CCUN
    Centro de Investigación Biomédica en Red Cáncer (CIBERONC))

  • Felipe Prósper

    (Universidad de Navarra, IDISNA, CCUN
    Centro de Investigación Biomédica en Red Cáncer (CIBERONC)
    Clínica Universidad de Navarra, and CCUN, Universidad de Navarra)

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.

Suggested Citation

  • 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 & , 2024. "Epigenetic-based differentiation therapy for Acute Myeloid Leukemia," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49784-y
    DOI: 10.1038/s41467-024-49784-y
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    References listed on IDEAS

    as
    1. Henry E. Pelish & Brian B. Liau & Ioana I. Nitulescu & Anupong Tangpeerachaikul & Zachary C. Poss & Diogo H. Da Silva & Brittany T. Caruso & Alexander Arefolov & Olugbeminiyi Fadeyi & Amanda L. Christ, 2015. "Mediator kinase inhibition further activates super-enhancer-associated genes in AML," Nature, Nature, vol. 526(7572), pages 273-276, October.
    2. Rashmi R. Shah, 2019. "Safety and Tolerability of Histone Deacetylase (HDAC) Inhibitors in Oncology," Drug Safety, Springer, vol. 42(2), pages 235-245, February.
    3. Johannes Zuber & Junwei Shi & Eric Wang & Amy R. Rappaport & Harald Herrmann & Edward A. Sison & Daniel Magoon & Jun Qi & Katharina Blatt & Mark Wunderlich & Meredith J. Taylor & Christopher Johns & A, 2011. "RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia," Nature, Nature, vol. 478(7370), pages 524-528, October.
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