Combination targeted therapy to disrupt aberrant oncogenic signaling and reverse epigenetic dysfunction in IDH2- and TET2-mutant acute myeloid leukemia

Cancer Discovery

Volumn 7, Issue 5, 2017, Pages 494-505

  Shih, Alan H ^a   Meydan, Cem ^b   Shank, Kaitlyn ^a   Garrett Bakelman, Francine E ^b   Ward, Patrick S ^a   Intlekofer, Andrew M ^a   Nazir, Abbas ^a   Stein, Eytan M ^a   Knapp, Kristina ^a   Glass, Jacob ^a,b   Travins, Jeremy ^c   Straley, Kim ^c   Gliser, Camelia ^c   Mason, Christopher E ^b   Yen, Katharine ^c   Thompson, Craig B ^a   Melnick, Ari ^b   Levine, Ross L ^a  

^a MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^b WEILL CORNELL MEDICAL COLLEGE   (United States)

^c AGIOS PHARMACEUTICALS   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 HYDROXYGLUTARIC ACID; AZACITIDINE; DIOXYGENASE; ENASIDENIB; ISOCITRATE DEHYDROGENASE 2; QUIZARTINIB; TET METHYLCYTOSINE DIOXYGENASE 2; UNCLASSIFIED DRUG; AG-221; AMINOPYRIDINE DERIVATIVE; ANTINEOPLASTIC AGENT; CD135 ANTIGEN; DNA BINDING PROTEIN; FLT3 PROTEIN, MOUSE; ISOCITRATE DEHYDROGENASE; ISOCITRATE DEHYDROGENASE 2, MOUSE; ONCOPROTEIN; TET2 PROTEIN, MOUSE; TRIAZINE DERIVATIVE;

ACUTE MYELOID LEUKEMIA; ANIMAL CELL; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BONE MARROW TRANSPLANTATION; CELL DIFFERENTIATION; DNA METHYLATION; EPIGENETICS; FLOW CYTOMETRY; FLUORESCENCE ACTIVATED CELL SORTING; GENE DISRUPTION; HEMATOPOIESIS; HIGH THROUGHPUT SEQUENCING; LIQUID CHROMATOGRAPHY-MASS SPECTROMETRY; MOLECULARLY TARGETED THERAPY; MOUSE; NONHUMAN; REDUCED REPRESENTATION BILSULFITE SEQUENCING; RNA SEQUENCE; ANIMAL; DRUG EFFECTS; GENETIC EPIGENESIS; GENETICS; MUTANT MOUSE STRAIN; MUTATION; PROCEDURES; SIGNAL TRANSDUCTION;

AMINOPYRIDINES; ANIMALS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; AZACITIDINE; DNA METHYLATION; DNA-BINDING PROTEINS; EPIGENESIS, GENETIC; FMS-LIKE TYROSINE KINASE 3; ISOCITRATE DEHYDROGENASE; LEUKEMIA, MYELOID, ACUTE; MICE; MICE, MUTANT STRAINS; MOLECULAR TARGETED THERAPY; MUTATION; PROTO-ONCOGENE PROTEINS; SIGNAL TRANSDUCTION; TRIAZINES;

EID: 85018430282     PISSN: 21598274     EISSN: 21598290     Source Type: Journal    
DOI: 10.1158/2159-8290.CD-16-1049     Document Type: Article

References (47)

1. Shih AH, Abdel-Wahab O, Patel JP, Levine RL. The role of mutations in epigenetic regulators in myeloid malignancies. Nat Rev Cancer 2012;12:599–612.
2. Dang L, Yen K, Attar EC. IDH mutations in cancer and progress toward development of targeted therapeutics. Ann Oncol 2016;27:599–608.
3. Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 2009;361:1058–66.
4. Rampal R, Alkalin A, Madzo J, Vasanthakumar A, Pronier E, Patel J, et al. DNA hydroxymethylation profiling reveals that WT1 mutations result in loss of TET2 function in acute myeloid leukemia. Cell Rep 2014;9:1841–55.
5. Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Masse A, et al. Mutation in TET2 in myeloid cancers. N Engl J Med 2009;360:2289–301.
6. Wang Y, Xiao M, Chen X, Chen L, Xu Y, Lv L, et al. WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation. Mol Cell 2015;57:662–73.
7. Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med 2010;363:2424–33.
8. 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;18:553–67.
9. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutaratedependent dioxygenases. Cancer Cell 2011;19:17–30.
10. Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 2009;324:930–5.
11. Patel JP, Gonen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012;366:1079–89.
12. CGARN CGARN. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013;368:2059–74.
13. Shen Y, Zhu YM, Fan X, Shi JY, Wang QR, Yan XJ, et al. Gene mutation patterns and their prognostic impact in a cohort of 1185 patients with acute myeloid leukemia. Blood 2011;118:5593–603.
14. Figueroa ME, Lugthart S, Li Y, Erpelinck-Verschueren C, Deng X, Christos PJ, et al. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell 2010;17:13–27.
15. Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D, Lobry C, et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 2011;20: 11–24.
16. Busque L, Patel JP, Figueroa ME, Vasanthakumar A, Provost S, Hamilou Z, et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet 2012;44:1179–81.
17. Jan M, Snyder TM, Corces-Zimmerman MR, Vyas P, Weissman IL, Quake SR, et al. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci Transl Med 2012;4:149ra18.
18. Shih AH, Jiang Y, Meydan C, Shank K, Pandey S, Barreyro L, et al. Mutational cooperativity linked to combinatorial epigenetic gain of function in acute myeloid leukemia. Cancer Cell 2015;27:502–15.
19. Chen C, Liu Y, Lu C, Cross JR, Morris JPT, Shroff AS, et al. Cancerassociated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition. Gen Dev 2013;27:1974–85.
20. 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;14:329–41.
21. Guryanova OA, Shank K, Spitzer B, Luciani L, Koche RP, Garrett- Bakelman FE, et al. DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling. Nat Med 2016;22:1488–95.
22. Nomdedeu J, Hoyos M, Carricondo M, Esteve J, Bussaglia E, Estivill C, et al. Adverse impact of IDH1 and IDH2 mutations in primary AML: experience of the Spanish CETLAM group. Leuk Res 2012;36: 990–7.
23. Chou WC, Chou SC, Liu CY, Chen CY, Hou HA, Kuo YY, et al. TET2 mutation is an unfavorable prognostic factor in acute myeloid leukemia patients with intermediate-risk cytogenetics. Blood 2011;118:3803–10.
24. Metzeler KH, Maharry K, Radmacher MD, Mrozek K, Margeson D, Becker H, et al. TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol 2011;29:1373–81.
25. Bejar R, Lord A, Stevenson K, Bar-Natan M, Perez-Ladaga A, Zaneveld J, et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood 2014;124:2705–12.
26. Itzykson R, Kosmider O, Cluzeau T, Mansat-De Mas V, Dreyfus F, Beyne-Rauzy O, et al. Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia 2011;25:1147–52.
27. Madzo J, Liu H, Rodriguez A, Vasanthakumar A, Sundaravel S, Caces DB, et al. Hydroxymethylation at gene regulatory regions directs stem/early progenitor cell commitment during erythropoiesis. Cell Rep 2014;6:231–44.
28. Pronier E, Almire C, Mokrani H, Vasanthakumar A, Simon A, da Costa Reis Monte Mor B, et al. Inhibition of TET2-mediated conversion of 5-methylcytosine to 5-hydroxymethylcytosine disturbs erythroid and granulomonocytic differentiation of human hematopoietic progenitors. Blood 2011;118:2551–5.
29. Akalin A, Garrett-Bakelman FE, Kormaksson M, Busuttil J, Zhang L, Khrebtukova I, et al. Base-pair resolution DNA methylation sequencing reveals profoundly divergent epigenetic landscapes in acute myeloid leukemia. PLoS Genet 2012;8:e1002781.
30. Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E, et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 2013;340:622–6.
31. Kernytsky A, Wang F, Hansen E, Schalm S, Straley K, Gliser C, et al. IDH2 mutation-induced histone and DNA hypermethylation is progressively reversed by small-molecule inhibition. Blood 2015;125: 296–303.
32. Stein EM. IDH2 inhibition in AML: Finally progress? Best Pract Res Clin Haematol 2015;28:112–5.
33. Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS, et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 2010;468:839–43.
34. Li L, Bailey E, Greenblatt S, Huso D, Small D. Loss of the wild-type allele contributes to myeloid expansion and disease aggressiveness in FLT3/ITD knockin mice. Blood 2011;118:4935–45.
35. Beerman I, Bock C, Garrison BS, Smith ZD, Gu H, Meissner A, et al. Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. Cell Stem Cell 2013;12: 413–25.
36. Hollenbach PW, Nguyen AN, Brady H, Williams M, Ning Y, Richard N, et al. A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines. PLoS One 2010;5:e9001.
37. Welch JS, Petti AA, Miller CA, Fronick CC, O’Laughlin M, Fulton RS, et al. TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. N Engl J Med 2016;375:2023–36.
38. Michor F, Hughes TP, Iwasa Y, Branford S, Shah NP, Sawyers CL, et al. Dynamics of chronic myeloid leukaemia. Nature 2005;435: 1267–70.
39. Mahon FX, Rea D, Guilhot J, Guilhot F, Huguet F, Nicolini F, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 2010;11:1029–35.
40. Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 2014;371:2488–98.
41. Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC, et al. Agerelated mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 2014;20:1472–8.
42. Shlush LI, Zandi S, Mitchell A, Chen WC, Brandwein JM, Gupta V, et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 2014;506:328–33.
43. Aimiuwu J, Wang H, Chen P, Xie Z, Wang J, Liu S, et al. RNA-dependent inhibition of ribonucleotide reductase is a major pathway for 5-azacytidine activity in acute myeloid leukemia. Blood 2012;119:5229–38.
44. Bhuvanagiri M, Lewis J, Putzker K, Becker JP, Leicht S, Krijgsveld J, et al. 5-azacytidine inhibits nonsense-mediated decay in a MYCdependent fashion. EMBO Mol Med 2014;6:1593–609.
45. Rose NR, McDonough MA, King ON, Kawamura A, Schofield CJ. Inhibition of 2-oxoglutarate dependent oxygenases. Chem Soc Rev 2011;40:4364–97.
46. Akalin A, Kormaksson M, Li S, Garrett-Bakelman FE, Figueroa ME, Melnick A, et al. methylKit: a comprehensive R package for the analysis of genome-wide DNA methylation profiles. Genome Biol 2012;13:R87.
47. Li S, Garrett-Bakelman FE, Akalin A, Zumbo P, Levine R, To BL, et al. An optimized algorithm for detecting and annotating regional differential methylation. BMC Bioinformatics 2013;14(Suppl 5):S10.