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Persistence of mutant isocitrate dehydrogenase in patients with acute myeloid leukemia in remission - Leukemia

  • ️Tien, H-F
  • ️Tue Aug 16 2011
  • Letter to the Editor
  • Published: 16 August 2011

Leukemia volume 26, pages 527–529 (2012)Cite this article

Isocitrate dehydrogenase (IDH1 and IDH2) mutations can be detected in brain tumors1, 2, 3 and acute myeloid leukemia (AML)4, 5, 6, 7 and are associated with distinct clinical and biological features. The mutations in these metabolic enzymes result in increase of 2-hydroxyglutarate (2HG) and decrease of α-ketoglutarate (α-KG), a cofactor of TET2, leading to disturbance of DNA and histone demethylation.8, 9 Consistent with these pathophysiological effects, IDH mutations are virtually mutually exclusive with loss-of-function mutations of TET2, which converts methylcytosine to hydroxymethylcytosine, a process probably related to DNA demethylation.8, 9 Taking the advantage of relative depletion of α-KG in IDH-mutated cells, which makes the cells more dependent on glutaminolysis pathway to supply α-KG, inhibition of this pathway by bis-2-5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a glutaminase inhibitor, has been shown to preferential kill IDH-mutated cells.10 Thus, the IDH mutations show a linkage between metabolism and cancers, demonstrate crosstalk between genetic and epigenetic dysregulation, and provide a well known pathway for possible targeted therapy. However, the role of IDH mutation in leukemogenesis remains to be defined. Here we show that IDH1 R132 and IDH2 R140 mutations can retain in myeloid but not lymphoid cells or skin tissue from three IDH-mutated AML patients in long-termed complete remission (CR), whereas the concomitant NPM1 or FLT3-ITD mutations are not detectable anymore.

We analyzed paired bone marrow samples collected at diagnosis, in CR, and at relapse in 19, 18 and 9 patients who harbored mutations at IDH1 R132, IDH2 R140 and IDH2 R172, respectively, using polymerase chain reaction followed by direct sequencing. A total of 114, 114 and 72 samples from these patients, respectively, were studied. The patients and materials were derived from our previous studies.4, 11 Screening for mutations of NPM1, IDH1/2 and FLT3-ITD was described previously.4, 11, 12 This study has been approved by the Institutional Review Board of the National Taiwan University Hospital.

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Acknowledgements

This work was supported by grants NSC 96-2628-B002-013-MY2, 97-2314-B002-015-MY3, 97-2628-B-002-002-MY3, 98-2314-B-002-033-MY3, 100-2325-B-002-032, 100-2325-B-002-033- from the National Science Council (Taiwan), NHRI-EX97-9731BI from the National Health Research Institute, DOH100-TD-C-111-001 from the Department of Health (Taiwan), NTUH 98-S1052, NTUH 98-S1383 from the National Taiwan University Hospital and the YongLin Healthcare Foundation.

Author contributions

W-CC and H-FT designed the experiment. W-CC, K-YP, C-HK and H-FT analyzed the data and wrote the paper. W-CL, B-SK and WT provided important materials.

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Authors and Affiliations

  1. Department of Laboratory Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan

    W-C Chou

  2. Department of Internal Medicine Division of Hematology, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan

    W-C Chou, W-C Lei, B-S Ko, W Tsay & H-F Tien

  3. The Metabolomics Core Laboratory, Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan

    K-Y Peng & C-H Kuo

  4. Institute of Environmental Health, College of Public Health, National Taiwan University, Taipei, Taiwan

    K-Y Peng

  5. Department of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan

    C-H Kuo

Authors

  1. W-C Chou

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  2. K-Y Peng

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  3. W-C Lei

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  4. B-S Ko

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  5. W Tsay

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  6. C-H Kuo

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  7. H-F Tien

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Correspondence to H-F Tien.

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Chou, WC., Peng, KY., Lei, WC. et al. Persistence of mutant isocitrate dehydrogenase in patients with acute myeloid leukemia in remission. Leukemia 26, 527–529 (2012). https://doi.org/10.1038/leu.2011.215

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  • Published: 16 August 2011

  • Issue Date: March 2012

  • DOI: https://doi.org/10.1038/leu.2011.215