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ACUTE MYELOID LEUKEMIA

MCL1 regulates AML cells metabolism via direct interaction with HK2. Metabolic signature at onset predicts overall survival in AMLs’ patients

Leukemia volume 37, pages 1600–1610 (2023)Cite this article

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Abstract

We characterize the metabolic background in distinct Acute Myeloid Leukemias (AMLs), by comparing the metabolism of primary AML blasts isolated at diagnosis with that of normal hematopoietic maturing progenitors, using the Seahorse XF Agilent. Leukemic cells feature lower spare respiratory (SRC) and glycolytic capacities as compared to hematopoietic precursors (i.e. day 7, promyelocytes). According with Proton Leak (PL) values, AML blasts can be grouped in two well defined populations. The AML group with blasts presenting high PL or high basal OXPHOS plus high SRC levels had shorter overall survival time and significantly overexpressed myeloid cell leukemia 1 (MCL1) protein. We demonstrate that MCL1 directly binds to Hexokinase 2 (HK2) on the outer mitochondrial membrane (OMM). Overall, these results suggest that high PL and high SRC plus high basal OXPHOS levels at disease onset, arguably with the concourse of MCL1/HK2 action, are significantly linked with shorter overall survival time in AML. Our data describe a new function for MCL1 protein in AMLs’ cells: by forming a complex with HK2, MCL1 co-localizes to VDAC on the OMM, thus inducing glycolysis and OXPHOS, ultimately conferring metabolic plasticity and promoting resistance to therapy.

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Fig. 1: Metabolic flux studies in AML primary blast and early progenitors/precursors (EP/P) from cultured normal cord blood CD34+ cells.
Fig. 2: AML patients with high mitochondrial respiration show worse overall survival.
Fig. 3: MCL1 expression and metabolic status in AML cells lines.
Fig. 4: Interaction between MCL1, HK2 and VDAC in OCI-AML3 cells.
Fig. 5: Proposed view of the functional role of the MCL1, HK2, VDAC complex in AML metabolisms.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This research was funded by AIRC 5 ×1000 call “Metastatic disease: the key unmet need in oncology” to MYNERVA project, #21267 (MYeloid NEoplasms Research Venture AIRC. A detailed description of the MYNERVA project is available at http://www.progettoagimm.it, accessed on 2 April 2022) to MTV, by PRIN 2017WXR7ZT_004 to MTV and by PRIN 2017WWB99Z to CN.

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Authors and Affiliations

  1. Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy

    Gianfranco Catalano, Alessandra Zaza, Serena Travaglini, Tiziana Ottone, Mariadomenica Divona, Maria Ilaria Del Principe, Francesco Buccisano, Luca Maurillo, Adriano Venditti, Maria Teresa Voso & Nelida Ines Noguera

  2. Santa Lucia Foundation, I.R.C.C.S. Via del Fosso di Fiorano, Rome, Italy

    Gianfranco Catalano, Alessandra Zaza, Cristina Banella, Ariela Smigliani, Serena Travaglini, Tiziana Ottone, Maria Teresa Voso & Nelida Ines Noguera

  3. Department of Health Sciences, University of Florence and Meyer Children’s University Hospital, Florence, Italy

    Cristina Banella

  4. Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy

    Elvira Pelosi, Germana Castelli & Ugo Testa

  5. Department of Medical and Surgical Sciences and Biotechnologies, University of Roma La Sapienza, Rome, Italy

    Elisabetta de Marinis

  6. Department of Hematology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Emanuele Ammatuna & Clara Nervi

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  1. Gianfranco Catalano
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  2. Alessandra Zaza
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Contributions

GC co-wrote the manuscript, contributed to study design and analyzed the results; AZ, CB, ST and AS performed experiments; TO, MD, IP, FB and LM obtained and characterized patient samples, updated the clinical data; EP, GC and UT provided cord blood samples, carried out the differentiation experiments of CD34+ progenitors; EdM, EA, CN and AV analyzed the data and co-wrote the manuscript, NIN and MTV contributed to study design, analyzed the experiments and co-wrote the manuscript. All authors have read and agreed with the content of the manuscript.

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Correspondence to Maria Teresa Voso or Nelida Ines Noguera.

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Catalano, G., Zaza, A., Banella, C. et al. MCL1 regulates AML cells metabolism via direct interaction with HK2. Metabolic signature at onset predicts overall survival in AMLs’ patients. Leukemia 37, 1600–1610 (2023). https://doi.org/10.1038/s41375-023-01946-5

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