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Metabolic profiling of measurable residual disease (MRD) in APL: Do MRD cells retain PML::RARα-mediated long-chain fatty acid (LCFA) dependency?

Leukemia (2026)Cite this article

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The Original Article was published on 10 September 2025

We read with great interest the study by Zaza et al., which provides a foundational characterization of metabolic reprogramming in PML::RARα+ acute promyelocytic leukemia (APL) [1]. Their work highlights a reliance on long-chain fatty acid (LCFA) catabolism as a key vulnerability. However, the study’s focus on bulk APL blasts at diagnosis overlooks the critical population of measurable residual disease (MRD) cells that drive clinical relapse in approximately 5% of patients [1]. A pivotal unanswered question is whether these persistent MRD cells retain the same PML::RARα-mediated LCFA dependency, an issue with direct implications for preventing disease recurrence.

MRD cells often exhibit metabolic properties distinct from bulk tumors as they adapt to survive therapy [2]. In other myeloid malignancies like acute myeloid leukemia (AML), MRD populations demonstrate enhanced oxidative phosphorylation (OXPHOS) [3], a metabolic state Zaza et al. describe for bulk APL blasts [1]. This suggests APL MRD cells might not only retain but potentially amplify their LCFA dependency. If confirmed, targeting LCFA uptake via CD36 inhibition, as proposed by the authors for arsenic trioxide-resistant clones [1], could represent a strategy to eliminate MRD and prevent relapse.

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References

  1. Zaza A, Zardo G, Banella C, Tucci S, de Marinis E, Gentile M, et al. PML::RARα+ myeloid cells display metabolic alterations that can be targeted to treat resistant/relapse acute promyelocytic leukemias. Leukemia. 2025;39:2708–20.

  2. Farge T, Saland E, de Toni F, Aroua N, Hosseini M, Perry R, et al. Chemotherapy-resistant human acute myeloid leukemia cells are not enriched for leukemic stem cells but require oxidative metabolism. Cancer Discov. 2017;7:716–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Jones CL, Stevens BM, Pollyea DA, Culp-Hill R, Reisz JA, Nemkov T, et al. Nicotinamide metabolism mediates resistance to venetoclax in relapsed acute myeloid leukemia stem cells. Cell Stem Cell. 2020;27:748–64.e4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Grønningsæter IS, Fredly HK, Gjertsen BT, Hatfield KJ, Bruserud Ø. Systemic metabolomic profiling of acute myeloid leukemia patients before and during disease-stabilizing treatment based on all-trans retinoic acid, valproic acid, and low-dose chemotherapy. Cells. 2019;8:1229.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Hindson BJ, Ness KD, Masquelier DA, Belgrader P, Heredia NJ, Makarewicz AJ, et al. High-throughput droplet digital PCR system for absolute quantitation of DNA copy number. Anal Chem. 2011;83:8604–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ye H, Adane B, Khan N, Sullivan T, Minhajuddin M, Gasparetto M, et al. Leukemic stem cells evade chemotherapy by metabolic adaptation to an adipose tissue niche. Cell Stem Cell. 2016;19:23–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Pollyea DA, Stevens BM, Jones CL, Winters A, Pei S, Minhajuddin M, et al. Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia. Nat Med. 2018;24:1859–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This study was supported by Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine.

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Authors and Affiliations

  1. Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Yu Zheng & Fangyi Dong

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  1. Yu Zheng
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  2. Fangyi Dong
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Yu Zheng and Fangyi Dong drafted the manuscript; Yu Zheng provided critical revisions.

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Correspondence to Yu Zheng.

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Zheng, Y., Dong, F. Metabolic profiling of measurable residual disease (MRD) in APL: Do MRD cells retain PML::RARα-mediated long-chain fatty acid (LCFA) dependency?. Leukemia (2026). https://doi.org/10.1038/s41375-025-02837-7

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