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CHRONIC LYMPHOCYTIC LEUKEMIA

ACOX1-mediated peroxisomal fatty acid oxidation contributes to metabolic reprogramming and survival in chronic lymphocytic leukemia

Leukemia volume 38, pages 302–317 (2024)Cite this article

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Abstract

Chronic lymphocytic leukemia (CLL) is still an incurable disease, with many patients developing resistance to conventional and targeted therapies. To better understand the physiology of CLL and facilitate the development of innovative treatment options, we examined specific metabolic features in the tumor CLL B-lymphocytes. We observed metabolic reprogramming, characterized by a high level of mitochondrial oxidative phosphorylation activity, a low glycolytic rate, and the presence of C2- to C6-carnitine end-products revealing an unexpected, essential role for peroxisomal fatty acid beta-oxidation (pFAO). Accordingly, downmodulation of ACOX1 (a rate-limiting pFAO enzyme overexpressed in CLL cells) was enough to shift the CLL cells’ metabolism from lipids to a carbon- and amino-acid-based phenotype. Complete blockade of ACOX1 resulted in lipid droplet accumulation and caspase-dependent death in CLL cells, including those from individuals with poor cytogenetic and clinical prognostic factors. In a therapeutic translational approach, ACOX1 inhibition spared non-tumor blood cells from CLL patients but led to the death of circulating, BCR-stimulated CLL B-lymphocytes and CLL B-cells receiving pro-survival stromal signals. Furthermore, a combination of ACOX1 and BTK inhibitors had a synergistic killing effect. Overall, our results highlight a less-studied but essential metabolic pathway in CLL and pave the way towards the development of new, metabolism-based treatment options.

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Fig. 1: Schematic representation of the three major metabolic pathways involved in OXPHOS energy production in CLL.
Fig. 2: Primary CLL B-cells show higher levels of mitochondrial respiration and lower levels of glycolytic activity than healthy B-cells.
Fig. 3: pFAO contributes to metabolic rewiring in CLL.
Fig. 4: Modulation of ACOX1 and pFAO induces metabolic reprogramming and lipid droplet accumulation in CLL cells.
Fig. 5: ACOX1/pFAO inhibition induces ATP loss and selectively targets circulating, BCR-stimulated CLL B-cells, and CLL B-cells receiving pro-survival stromal signals.
Fig. 6: ACOX1/pFAO inhibition induced mitochondrion-mediated caspase-3-dependent apoptosis in primary CLL B-cells.
Fig. 7: A combination of ACOX1/pFAO and BTK inhibitors has a synergistic killing effect on circulating and BCR-stimulated primary CLL B-cells.

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Data are available within the manuscript, figures, or supplementary information. Further correspondence and material requests should be addressed to the corresponding author. Source data are provided with this paper.

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Acknowledgements

Association Laurette Fugain (ALF 2020/08), Ligue Contre le Cancer-Comité de Paris (RS20/75-66 and RS19/75-59), Cancéropôle IDF (2021-1-EMERG-49-INSERM 6-1), and GEFLUC-Les Entreprises contre le Cancer, Paris Ile de France support this work. M. T. received PhD fellowships from SIRIC-CURAMUS (Cancer United research Associating Medecine, University and Society; grant reference: INCa-DGOS-INSERM_12560 and INCa-DGOS-INSERM-ITMO Cancer_18010) and Société Française d’Hématologie (SFH). M. A. holds a PhD support from Université Paris-Saclay. L.D. and K. D. received fellowships from SIRIC-CURAMUS. The authors thank Dr. Anne-Cécile Boulay (Center for Interdisciplinary Research in Biology, College de France) for statistical advice and Noémie Robil (GenoSplice technology) for RNAseq bioinformatics analyses. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Author notes

  1. These authors contributed equally: Marianne Ayoub, Léa Dehgane.

  2. These authors jointly supervised this work: Delphine Garnier, Santos A. Susin.

Authors and Affiliations

  1. Centre de Recherche des Cordeliers, Sorbonne Université, Université Paris Cité, Inserm UMRS 1138, Drug Resistance in Hematological Malignancies Team, F-75006, Paris, France

    Mariana Tannoury, Marianne Ayoub, Léa Dehgane, Kenza Dubois, Aurélie Brousse, Damien Roos-Weil, Karim Maloum, Hélène Merle-Béral, Brigitte Bauvois, Elise Chapiro, Florence Nguyen-Khac, Delphine Garnier & Santos A. Susin

  2. Structure Fédérative de Recherche Necker, INSERM US24/CNRS UAR 3633, Platform for Metabolic Analyses, F-75015, Paris, France

    Ivan Nemazanyy

  3. Faculté de Pharmacie, Université Paris Cité, PICMO, US 25 Inserm, UAR 3612 CNRS, F-75006, Paris, France

    Charlotte Izabelle & Bruno Saubamea

  4. Sorbonne Université, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Service d’Hématologie Clinique, F-75013, Paris, France

    Damien Roos-Weil

  5. Sorbonne Université, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Service d’Hématologie Biologique, F-75013, Paris, France

    Karim Maloum, Elise Chapiro & Florence Nguyen-Khac

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  1. Mariana Tannoury
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MT conceived and performed CLL experimental work, analyzed the data, and helped to write the manuscript. MA and LD conceived and performed CLL experimental work and analyzed the data. IN performed metabolomic studies, analyzed the data, and helped in metabolomic profile presentation. KD performed CLL/stromal cell coculture approaches and analyzed the data. CI performed electronic microscopy and analyzed the results. AB performed immunofluorescence and analyzed the results. DR-W and KM provided CLL samples and critical advice. HM-B and BB provided critical advice on the work and the manuscript. BS conceived and performed electronic microscopy work, and analyzed the data. EC performed cytogenetic analysis, completed the mutational status and karyotype of the CLL patients, and provided critical advice throughout the study. FN-K provided CLL samples, performed cytogenetic analysis, and provided critical advice throughout the study. DG conceived and supervised experimental work, analyzed the data, provided critical advice throughout the study, and helped to write the manuscript. SAS conceived and supervised all aspects of the project, designed experiments, interpreted the data, and wrote the manuscript. All authors reviewed and approved the manuscript.

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Correspondence to Santos A. Susin.

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Patient samples were collected after informed consent according to the Declaration of Helsinki.

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Tannoury, M., Ayoub, M., Dehgane, L. et al. ACOX1-mediated peroxisomal fatty acid oxidation contributes to metabolic reprogramming and survival in chronic lymphocytic leukemia. Leukemia 38, 302–317 (2024). https://doi.org/10.1038/s41375-023-02103-8

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