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A pharmacogenomic approach validates AG-221 as an effective and on-target therapy in IDH2 mutant AML

Leukemia volume 31, pages 1466–1470 (2017)Cite this article

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Acute myeloid leukemia (AML) is a disease with poor prognosis and novel treatment strategies to improve patient outcomes are urgently required. Approximately 20% of AML patients carry mutations in genes that encode the metabolic enzymes isocitrate dehydrogenase (IDH) 1 and -2.1, 2 Mutant IDH proteins possess a neomorphic enzymatic activity and produce the onco-metabolite D-2-hydroxyglutarate (2-HG) that modulates pathways implicated in cell-fate decisions and cancer.3, 4, 5, 6, 7, 8 Mutant IDH proteins can contribute to malignant transformation;9, 10 however, their role in continued survival and proliferation of established leukemias remains poorly understood. Small molecule inhibitors of IDH1 and -2 have recently entered clinical trials11 and there is a need to delineate how these drugs behave in physiologically relevant pre-clinical models.

To determine whether genetic inactivation of IDH2R140Q in IDN cells has an impact on disease maintenance and/or progression we performed randomized de-induction experiments. Mice transplanted with primary IDN leukemic cells were administered doxycycline to silence expression of the conditional IDH2R140Q allele (Supplementary Figures S1d and S2a). After seven days of treatment we observed evidence of terminal myeloid differentiation as indicated by the acquisition of the mature myeloid marker Gr1 (Supplementary Figure S2b) concomitant with an initial increase in the number of leukemic cells in the peripheral blood within the first week of treatment, followed by a rapid regression by week two (Supplementary Figure S2c). This is similar to differentiation syndrome observed in acute promyelocytic leukemia patients treated with all trans-retinoic acid; and has also been noted in IDH1 mutant patients treated with the IDH1 inhibitor AG-120.12 De-induction of IDH2R140Q resulted in increased median survival of syngeneic (Ptprca) and immune-compromised (NSG) secondary recipients by ⩾50% (Supplementary Figure S2d–f).

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References

  1. The Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013; 368: 2059–2074.

    Article  Google Scholar 

  2. Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med 2016; 374: 2209–2221.

    Article  CAS  Google Scholar 

  3. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009; 462: 739–744.

    Article  CAS  Google Scholar 

  4. Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting α-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 2010; 17: 225–234.

    Article  CAS  Google Scholar 

  5. Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 2010; 18: 553–567.

    Article  CAS  Google Scholar 

  6. Koivunen P, Lee S, Duncan CG, Lopez G, Lu G, Ramkissoon S et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 2012; 483: 484–488.

    Article  CAS  Google Scholar 

  7. Inoue S, Li WY, Tseng A, Beerman I, Elia AJ, Bendall SC et al. Mutant IDH1 downregulates ATM and alters DNA repair and sensitivity to DNA damage independent of TET2. Cancer Cell 2016; 30: 337–348.

    Article  CAS  Google Scholar 

  8. Cairns RA, Mak TW . Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities. Cancer Discov 2013; 3: 730–741.

    Article  CAS  Google Scholar 

  9. Chen C, Liu Y, Lu C, Cross JR, Morris JP, Shroff AS et al. Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition. Genes Dev 2013; 27: 1974–1985.

    Article  CAS  Google Scholar 

  10. Kats LM, Reschke M, Taulli R, Pozdnyakova O, Burgess K, Bhargava P et al. Proto-oncogenic role of mutant IDH2 in leukemia initiation and maintenance. Cell Stem Cell 2014; 14: 329–341.

    Article  CAS  Google Scholar 

  11. Stein EM . IDH2 inhibition in AML: finally progress? Best Pract Res Clin Haematol 2015; 28: 112–115.

    Article  Google Scholar 

  12. Birendra KC, DiNardo CD . Evidence for clinical differentiation and differentiation syndrome in patients with acute myeloid leukemia and IDH1 mutations treated with the targeted mutant IDH1 inhibitor, AG-120. Clin Lymphoma Myeloma Leuk 2016; 16: 460–465.

    Article  CAS  Google Scholar 

  13. Graham SM, Vass JK, Holyoake TL, Graham GJ . Transcriptional analysis of quiescent and proliferating CD34+ human hemopoietic cells from normal and chronic myeloid leukemia sources. Stem Cells 2007; 25: 3111–3120.

    Article  CAS  Google Scholar 

  14. Ivanova NB, Dimos JT, Schaniel C, Hackney JA, Moore KA, Lemischka IR . A stem cell molecular signature. Science 2002; 298: 601–604.

    Article  CAS  Google Scholar 

  15. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 2005; 102: 15545–15550.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was funded by project and program grants (RWJ and LMK) from the National Health and Medical Research Council of Australia (NHMRC) and a grant from the Peter Mac Foundation (LMK). RWJ was supported by an NHMRC Fellowship and LMK was supported by a Victorian Cancer Agency fellowship.

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Authors and Affiliations

  1. Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    L M Kats, S J Vervoort, R Cole, A J Rogers, G P Gregory, E Vidacs & R W Johnstone

  2. The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia

    L M Kats, G P Gregory, J Li & R W Johnstone

  3. Monash Haematology, Monash Health and School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia

    G P Gregory

  4. Bioinformatics Core, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    J Li

  5. Agios Pharmaceuticals, Cambridge, MA, USA

    R Nagaraja & K E Yen

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Correspondence to L M Kats or R W Johnstone.

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RN and KEY are employees of and have ownership interest (including some with patents) in Agios Pharmaceuticals. The remaining authors declare no conflict of interest.

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Kats, L., Vervoort, S., Cole, R. et al. A pharmacogenomic approach validates AG-221 as an effective and on-target therapy in IDH2 mutant AML. Leukemia 31, 1466–1470 (2017). https://doi.org/10.1038/leu.2017.84

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