Blood Res.  2022 Mar;57(1):13-19. 10.5045/br.2021.2021152.

IDH1/2 mutations in acute myeloid leukemia

• Byun JM
• Yoo SJ
• Kim HJ
• Ahn JS
• Koh Y
• Jang JH
• Yoon SS

• KMID: 2527492
• DOI: http://doi.org/10.5045/br.2021.2021152

Abstract

The mutational and epigenetic landscape of acute myeloid leukemia (AML) has become increasingly well understood in recent years, informing on biological targets for precision medicine. Among the most notable findings was the recognition of mutational hot-spots in the isocitrate dehydrogenase (IDH) genes. In this review, we provide an overview on the IDH1/2 mutation landscape in Korean AML patients, and compare it with available public data. We also discuss the role of IDH1/2 mutations as biomarkers and drug targets. Taken together, occurrence of IDH1/2 mutations is becoming increasingly important in AML treatment, thus requiring thorough examination and follow-up throughout the clinical course of the disease.

Keyword

Acute myeloid leukemia; IDH; Biomarker; Drug target; Korean

Figure

• 

  Fig. 1 (A) Oncoprint with mutation-profiled Korean acute myeloid leukemia samples. Blue: missense mutation, pink: frameshift insertion, sky blue: frameshift deletion, and green: multi-hit. Mutations listed in the COSMIC database are marked with grey dots. (B) Oncoprint obtained from cBioPortal. Clinical and genomic data (622 from OHSU and 200 from TCGA) were merged.

• 

  Fig. 2 (A) Co-occurrence plot displaying interactions between genes in Korean patients. Red indicates higher degree of co-occurrence between two genes, while blue indicates higher degree of mutual exclusiveness. P-values from each Fisher’s exact test are grouped into five groups, and the groups with P>0.05 are not displayed. The remaining four groups with P<0.05 are displayed on a scale for each section. In the case that the absolute value of log2 odds ratio was at least 1 and the P-value is marked, the box’s margin is marked black. When mutations of two genes did not occur in one sample, the odds ratio could not be calculated, therefore, many mutual exclusive interactions identified in Fig. 1A are not shown in this plot. (B) Co-occurrence plot using publicly available data matching with Fig. 1B. The number of patients is larger than the Korean cohort. Accordingly, a higher number of mutually exclusive signals were detected in the public database than in the Korean cohort.

• 

  Fig. 3 (A) Oncoplot showing Korean patients with FLT3, NPM1, DNMT3A, IDH1 and IDH2 mutations. Hotspots are shown for IDH1 and IDH2. (B) Interactions between five genes from Korean AML patients shown in the same way as previously displayed. (C) Oncoplots using public data from cBioPortal regarding five genes. (D) Interactions between five genes from samples from cBioPortal shown in the same way as previously displayed. In cases of white color boxes and P-value marking, odds ratio is zero because there are no events of mutations in both genes.

Reference

1. Mardis ER, Ding L, Dooling DJ, et al. 2009; Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 361:1058–66. DOI: 10.1056/NEJMoa0903840. PMID: 19657110. PMCID: PMC3201812.

2. Ley TJ, Miller C, et al. Cancer Genome Atlas Research Network. 2013; Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 368:2059–74. DOI: 10.1056/NEJMoa1301689. PMID: 23634996. PMCID: PMC3767041.

3. Papaemmanuil E, Gerstung M, Bullinger L, et al. 2016; Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 374:2209–21. DOI: 10.1056/NEJMoa1516192. PMID: 27276561. PMCID: PMC4979995.

4. Dang L, Yen K, Attar EC. 2016; IDH mutations in cancer and progress toward development of targeted therapeutics. Ann Oncol. 27:599–608. DOI: 10.1093/annonc/mdw013. PMID: 27005468.

5. Clark O, Yen K, Mellinghoff IK. 2016; Molecular pathways: isocitrate dehydrogenase mutations in cancer. Clin Cancer Res. 22:1837–42. DOI: 10.1158/1078-0432.CCR-13-1333. PMID: 26819452. PMCID: PMC4834266.

6. Molenaar RJ, Radivoyevitch T, Maciejewski JP, van Noorden CJ, Bleeker FE. 2014; The driver and passenger effects of isocitrate dehydrogenase 1 and 2 mutations in oncogenesis and survival prolongation. Biochim Biophys Acta. 1846:326–41. DOI: 10.1016/j.bbcan.2014.05.004. PMID: 24880135.

7. Yang H, Ye D, Guan KL, Xiong Y. 2012; IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Clin Cancer Res. 18:5562–71. DOI: 10.1158/1078-0432.CCR-12-1773. PMID: 23071358. PMCID: PMC3897211.

8. Montalban-Bravo G, DiNardo CD. 2018; The role of IDH mutations in acute myeloid leukemia. Future Oncol. 14:979–93. DOI: 10.2217/fon-2017-0523. PMID: 29543066.

9. Aref S, Kamel Areida el S, Abdel Aaal MF, et al. 2015; Prevalence and clinical effect of IDH1 and IDH2 mutations among cytogenetically normal acute myeloid leukemia patients. Clin Lymphoma Myeloma Leuk. 15:550–5. DOI: 10.1016/j.clml.2015.05.009. PMID: 26189213.

10. Kranendijk M, Struys EA, van Schaftingen E, et al. 2010; IDH2 mutations in patients with D-2-hydroxyglutaric aciduria. Science. 330:336. DOI: 10.1126/science.1192632. PMID: 20847235.

11. Dang L, White DW, Gross S, et al. 2010; Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 465:966. DOI: 10.1038/nature09132. PMID: 20559394. PMCID: PMC3766976.

12. Ye D, Ma S, Xiong Y, Guan KL. 2013; R-2-hydroxyglutarate as the key effector of IDH mutations promoting oncogenesis. Cancer Cell. 23:274–6. DOI: 10.1016/j.ccr.2013.03.005. PMID: 23518346. PMCID: PMC3652525.

13. Lu C, Ward PS, Kapoor GS, et al. 2012; IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 483:474–8. DOI: 10.1038/nature10860. PMID: 22343901. PMCID: PMC3478770.

14. Chaturvedi A, Araujo Cruz MM, Jyotsana N, et al. 2016; Enantiomer-specific and paracrine leukemogenicity of mutant IDH metabolite 2-hydroxyglutarate. Leukemia. 30:1708–15. DOI: 10.1038/leu.2016.71. PMID: 27063596. PMCID: PMC5298178.

15. Molenaar RJ, Thota S, Nagata Y, et al. 2015; Clinical and biological implications of ancestral and non-ancestral IDH1 and IDH2 mutations in myeloid neoplasms. Leukemia. 29:2134–42. DOI: 10.1038/leu.2015.91. PMID: 25836588. PMCID: PMC5821256.

16. Shlush LI, Zandi S, Mitchell A, et al. 2014; Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature. 506:328–33. DOI: 10.1038/nature13038. PMID: 24522528. PMCID: PMC4991939.

17. Xie M, Lu C, Wang J, et al. 2014; Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 20:1472–8. DOI: 10.1038/nm.3733. PMID: 25326804. PMCID: PMC4313872.

18. Malcovati L, Gallì A, Travaglino E, et al. 2017; Clinical significance of somatic mutation in unexplained blood cytopenia. Blood. 129:3371–8. DOI: 10.1182/blood-2017-01-763425. PMID: 28424163. PMCID: PMC5542849.

19. Li H, Durbin R. 2010; Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 26:589–95. DOI: 10.1093/bioinformatics/btp698. PMID: 20080505. PMCID: PMC2828108.

20. McKenna A, Hanna M, Banks E, et al. 2010; The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20:1297–303. DOI: 10.1101/gr.107524.110. PMID: 20644199. PMCID: PMC2928508.

21. Wang K, Li M, Hakonarson H. 2010; ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 38:e164. DOI: 10.1093/nar/gkq603. PMID: 20601685. PMCID: PMC2938201.

22. Howe KL, Achuthan P, Allen J, et al. 2021; Ensembl 2021. Nucleic Acids Res. 49:D884–91. DOI: 10.1093/nar/gkaa942. PMID: 33137190. PMCID: PMC7778975.

23. Auton A, Brooks LD, et al. 1000 Genomes Project Consortium. 2015; A global reference for human genetic variation. Nature. 526:68–74. DOI: 10.1038/nature15393. PMID: 26432245. PMCID: PMC4750478.

24. Landrum MJ, Lee JM, Benson M, et al. 2018; ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 46:D1062–7. DOI: 10.1093/nar/gkx1153. PMID: 29165669. PMCID: PMC5753237.

25. Tate JG, Bamford S, Jubb HC, et al. 2019; COSMIC: the catalogue of somatic mutations in cancer. Nucleic Acids Res. 47:D941–7. DOI: 10.1093/nar/gky1015. PMID: 30371878. PMCID: PMC6323903.

26. R Core Team. 2013. R: a language and environment for statistical computing. R Foundation for Statistical Computing;Vienna, Austria: at https://www.R-project.org/. Accessed November 11, 2021.

27. Wickham H. 2016. ggplot2: elegant graphics for data analysis. 2nd ed. Springer;Cham, Switzerland: DOI: 10.1007/978-3-319-24277-4.

28. Nowosad J, Stepinski TF. 2021; Pattern-based identification and mapping of landscape types using multi-thematic data. Int J Geogr Inf Sci. 35:1634–49. DOI: 10.1080/13658816.2021.1893324.

29. Tyner JW, Tognon CE, Bottomly D, et al. 2018; Functional genomic landscape of acute myeloid leukaemia. Nature. 562:526–31. DOI: 10.1038/s41586-018-0623-z. PMID: 30333627. PMCID: PMC6280667.

30. Boddu P, Takahashi K, Pemmaraju N, et al. 2017; Influence of IDH on FLT3-ITD status in newly diagnosed AML. Leukemia. 31:2526–9. DOI: 10.1038/leu.2017.244. PMID: 28751773.

31. Cerami E, Gao J, Dogrusoz U, et al. 2012; The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2:401–4. DOI: 10.1158/2159-8290.CD-12-0095. PMID: 22588877. PMCID: PMC3956037.

32. Xu Q, Li Y, Lv N, et al. 2017; Correlation between isocitrate dehydrogenase gene aberrations and prognosis of patients with acute myeloid leukemia: a systematic review and meta-analysis. Clin Cancer Res. 23:4511–22. DOI: 10.1158/1078-0432.CCR-16-2628. PMID: 28246275.

33. Paschka P, Schlenk RF, Gaidzik VI, et al. 2010; IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol. 28:3636–43. DOI: 10.1200/JCO.2010.28.3762. PMID: 20567020.

34. Patel JP, Gönen M, Figueroa ME, et al. 2012; Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 366:1079–89. DOI: 10.1056/NEJMoa1112304. PMID: 22417203. PMCID: PMC3545649.

35. DiNardo CD. 2018; Ivosidenib in IDH1-mutated acute myeloid leukemia. N Engl J Med. 379:1186. DOI: 10.1056/NEJMc1809507. PMID: 30260155.

36. DiNardo CD, Stein EM, de Botton S, et al. 2018; Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 378:2386–98. DOI: 10.1056/NEJMoa1716984. PMID: 29860938.

37. Yen K, Travins J, Wang F, et al. 2017; AG-221, a first-in-class therapy targeting acute myeloid leukemia harboring oncogenic IDH2 mutations. Cancer Discov. 7:478–93. DOI: 10.1158/2159-8290.CD-16-1034. PMID: 28193778.

38. Stein EM, Fathi AT, DiNardo CD, et al. 2020; Enasidenib in patients with mutant IDH2 myelodysplastic syndromes: a phase 1 subgroup analysis of the multicentre, AG221-C-001 trial. Lancet Haematol. 7:e309–19. DOI: 10.1016/S2352-3026(19)30284-4. PMID: 32145771.

39. Stein EM, DiNardo CD, Pollyea DA, et al. 2017; Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 130:722–31. DOI: 10.1182/blood-2017-04-779405. PMID: 28588020. PMCID: PMC5572791.

40. Chaturvedi A, Araujo Cruz MM, Jyotsana N, et al. 2013; Mutant IDH1 promotes leukemogenesis in vivo and can be specifically targeted in human AML. Blood. 122:2877–87. DOI: 10.1182/blood-2013-03-491571. PMID: 23954893.

41. Sulkowski PL, Corso CD, Robinson ND, et al. 2017; 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci Transl Med. 9:eaal2463. DOI: 10.1126/scitranslmed.aal2463. PMID: 28148839. PMCID: PMC5435119.