Cooperative Epigenetic Remodeling by TET2 Loss and NRAS Mutation Drives Myeloid Transformation and MEK Inhibitor Sensitivity

Cancer Cell

Volumn 33, Issue 1, 2018, Pages 44-59.e8

  Kunimoto, Hiroyoshi ^a   Meydan, Cem ^b   Nazir, Abbas ^a   Whitfield, Justin ^a   Shank, Kaitlyn ^a   Rapaport, Franck ^a   Maher, Rebecca ^c   Pronier, Elodie ^a   Meyer, Sara C ^d   Garrett Bakelman, Francine E ^b,e   Tallman, Martin ^a   Melnick, Ari ^b   Levine, Ross L ^a   Shih, Alan H ^a  

^a MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^b WEILL CORNELL MEDICAL COLLEGE   (United States)

^c UNIVERSITY OF CONNECTICUT SCHOOL OF MEDICINE   (United States)

^d UNIVERSITY HOSPITAL BASEL   (Switzerland)

^e UNIVERSITY OF VIRGINIA   (United States)

Author keywords

cancer epigenetics; leukemia biology; targeted therapeutics

Indexed keywords

BINIMETINIB; MITOGEN ACTIVATED PROTEIN KINASE KINASE INHIBITOR; N (2,3 DIHYDROXYPROPOXY) 3,4 DIFLUORO 2 (2 FLUORO 4 IODOANILINO)BENZAMIDE; SELUMETINIB; DNA BINDING PROTEIN; GUANOSINE TRIPHOSPHATASE; MEMBRANE PROTEIN; MONOMERIC GUANINE NUCLEOTIDE BINDING PROTEIN; N-RAS PROTEIN, MOUSE; NRAS PROTEIN, HUMAN; ONCOPROTEIN; SIGNAL PEPTIDE; SPRY2 PROTEIN, MOUSE; TET2 PROTEIN, HUMAN; TET2 PROTEIN, MOUSE;

ADULT; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CHILD; CHRONIC MYELOMONOCYTIC LEUKEMIA; CONTROLLED STUDY; ENZYME ACTIVATION; EPIGENETICS; FEMALE; GENE LOSS; GENE MUTATION; GENE SILENCING; HEMATOPOIETIC CELL; HUMAN; HUMAN CELL; MALE; MALIGNANT TRANSFORMATION; MAPK SIGNALING; MOLM-13 CELL LINE; MOUSE; NONHUMAN; ONCOGENE; ONCOGENE N RAS; PRESCHOOL CHILD; PRIORITY JOURNAL; TET2 GENE; THP-1 CELL LINE; YOUNG ADULT; ANIMAL; CELL TRANSFORMATION; GENETICS; MUTATION; MYELOPROLIFERATIVE DISORDER; SIGNAL TRANSDUCTION; TRANSGENIC MOUSE;

ANIMALS; CELL TRANSFORMATION, NEOPLASTIC; DNA-BINDING PROTEINS; GTP PHOSPHOHYDROLASES; HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; LEUKEMIA, MYELOMONOCYTIC, CHRONIC; MEMBRANE PROTEINS; MICE, TRANSGENIC; MONOMERIC GTP-BINDING PROTEINS; MUTATION; MYELOPROLIFERATIVE DISORDERS; PROTO-ONCOGENE PROTEINS; SIGNAL TRANSDUCTION;

EID: 85038841424     PISSN: 15356108     EISSN: 18783686     Source Type: Journal    
DOI: 10.1016/j.ccell.2017.11.012     Document Type: Article

References (48)

1. Abdel-Wahab, O., Mullally, A., Hedvat, C., Garcia-Manero, G., Patel, J., Wadleigh, M., Malinge, S., Yao, J., Kilpivaara, O., Bhat, R., et al. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 114 (2009), 144–147.
2. Abdel-Wahab, O., Adli, M., LaFave, L.M., Gao, J., Hricik, T., Shih, A.H., Pandey, S., Patel, J.P., Chung, Y.R., Koche, R., et al. ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell 22 (2012), 180–193.
3. Amatangelo, M.D., Quek, L., Shih, A., Stein, E.M., Roshal, M., David, M.D., Marteyn, B., Farnoud, N.R., de Botton, S., Bernard, O.A., et al. Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood 130 (2017), 732–741.
4. Ascierto, P.A., Schadendorf, D., Berking, C., Agarwala, S.S., van Herpen, C.M., Queirolo, P., Blank, C.U., Hauschild, A., Beck, J.T., St-Pierre, A., et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol. 14 (2013), 249–256.
5. Bacher, U., Haferlach, T., Schoch, C., Kern, W., Schnittger, S., Implications of NRAS mutations in AML: a study of 2502 patients. Blood 107 (2006), 3847–3853.
6. Borthakur, G., Popplewell, L., Boyiadzis, M., Foran, J., Platzbecker, U., Vey, N., Walter, R.B., Olin, R., Raza, A., Giagounidis, A., et al. Activity of the oral mitogen-activated protein kinase kinase inhibitor trametinib in RAS-mutant relapsed or refractory myeloid malignancies. Cancer 122 (2016), 1871–1879.
7. Burgess, M.R., Hwang, E., Firestone, A.J., Huang, T., Xu, J., Zuber, J., Bohin, N., Wen, T., Kogan, S.C., Haigis, K.M., et al. Preclinical efficacy of MEK inhibition in Nras-mutant AML. Blood 124 (2014), 3947–3955.
8. Burgess, M.R., Hwang, E., Mroue, R., Bielski, C.M., Wandler, A.M., Huang, B.J., Firestone, A.J., Young, A., Lacap, J.A., Crocker, L., et al. KRAS allelic imbalance enhances fitness and modulates MAP kinase dependence in cancer. Cell 168 (2017), 817–829.
9. Busque, L., Patel, J.P., Figueroa, M.E., Vasanthakumar, A., Provost, S., Hamilou, Z., Mollica, L., Li, J., VIale, A., Heguy, A., et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat. Genet. 44 (2012), 1179–1181.
10. Cancer Genome Atlas Research Network, Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 368 (2013), 2059–2074.
11. Chang, Y.I., Damnernsawad, A., Allen, L.K., Yang, D., Ranheim, E.A., Young, K.H., Zhang, J., Kong, G., Wang, J., Liu, Y., et al. Evaluation of allelic strength of human TET2 mutations and cooperation between Tet2 knockdown and oncogenic Nras mutation. Br. J. Haematol. 166 (2014), 461–465.
12. Cichowski, K., Jacks, T., NF1 tumor suppressor gene function: narrowing the GAP. Cell 104 (2001), 593–604.
13. Delhommeau, F., Dupont, S., Della Valle, V., James, C., Trannoy, S., Massé, A., Kosmider, O., Le Couedic, J.P., Robert, F., Alberdi, A., et al. Mutation in TET2 in myeloid cancers. N. Engl. J. Med. 360 (2009), 2289–2301.
14. Edwin, F., Anderson, K., Ying, C., Patel, T.B., Intermolecular interactions of Sprouty proteins and their implications in development and disease. Mol. Pharmacol. 76 (2009), 679–691.
15. Elena, C., Gallì, A., Such, E., Meggendorfer, M., Germing, U., Rizzo, E., Cervera, J., Molteni, E., Fasan, A., Schuler, E., et al. Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia. Blood 128 (2016), 1408–1417.
16. Frank, M.J., Dawson, D.W., Bensinger, S.J., Hong, J.S., Knosp, W.M., Xu, L., Balatoni, C.E., Allen, E.L., Shen, R.R., Bar-Sagi, D., et al. Expression of sprouty2 inhibits B-cell proliferation and is epigenetically silenced in mouse and human B-cell lymphomas. Blood 113 (2009), 2478–2487.
17. Genovese, G., Kähler, A.K., Handsaker, R.E., Lindberg, J., Rose, S.A., Bakhoum, S.F., Chambert, K., Mick, E., Neale, B.M., Fromer, M., et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371 (2014), 2477–2487.
18. Haigis, K.M., Kendall, K.R., Wang, Y., Cheung, A., Haigis, M.C., Glickman, J.N., Niwa-Kawakita, M., Sweet-Cordero, A., Sebolt-Leopold, J., Shannon, K.M., et al. Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nat. Genet. 40 (2008), 600–608.
19. Hercus, T.R., Thomas, D., Guthridge, M.A., Ekert, P.G., King-Scott, J., Parker, M.W., Lopez, A.F., The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease. Blood 114 (2009), 1289–1298.
20. Itzykson, R., Kosmider, O., Renneville, A., Morabito, M., Preudhomme, C., Berthon, C., Adès, L., Fenaux, P., Platzbecker, U., Gagey, O., et al. Clonal architecture of chronic myelomonocytic leukemias. Blood 121 (2013), 2186–2198.
21. Jaiswal, S., Fontanillas, P., Flannick, J., Manning, A., Grauman, P.V., Mar, B.G., Lindsley, R.C., Mermel, C.H., Burtt, N., Chavez, A., et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371 (2014), 2488–2498.
22. Jan, M., Snyder, T.M., Corces-Zimmerman, M.R., Vyas, P., Weissman, I.L., Quake, S.R., Majeti, R., Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci. Transl. Med., 4, 2012, 149ra118.
23. Jankowska, A.M., Szpurka, H., Tiu, R.V., Makishima, H., Afable, M., Huh, J., O'Keefe, C.L., Ganetzky, R., McDevitt, M.A., Maciejewski, J.P., Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms. Blood 113 (2009), 6403–6410.
24. Jänne, P.A., Shaw, A.T., Pereira, J.R., Jeannin, G., Vansteenkiste, J., Barrios, C., Franke, F.A., Grinsted, L., Zazulina, V., Smith, P., et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomized, multicenter, placebo-controlled, phase 2 study. Lancet Oncol. 14 (2013), 38–47.
25. Janssen, J.W., Steenvoorden, A.C., Lyons, J., Anger, B., Böhlke, J.U., Bos, J.L., Seliger, H., Bartram, C.R., RAS gene mutations in acute and chronic myelocytic leukemias, chronic myeloproliferative disorders, and myelodysplastic syndromes. Proc. Natl. Acad. Sci. USA 84 (1987), 9228–9232.
26. Khanna, V., Pierce, S.T., Dao, K.H., Tognon, C.E., Hunt, D.E., Junio, B., Tyner, J.W., Druker, B.J., Durable disease control with MEK inhibition in a patient with NRAS-mutated atypical chronic myeloid leukemia. Cureus, 7, 2015, e414.
27. Kogan, S.C., Ward, J.M., Anver, M.R., Berman, J.J., Brayton, C., Cardiff, R.D., Carter, J.S., de Coronado, S., Downing, J.R., Fredrickson, T.N., et al. Bethesda proposals for classification of nonlymphoid hematopoietic neoplasms in mice. Blood 100 (2002), 238–245.
28. Langemeijer, S.M., Kuiper, R.P., Berends, M., Knops, R., Aslanyan, M.G., Massop, M., Stevens-Linders, E., van Hoogen, P., van Kessel, A.G., Raymakers, R.A., et al. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat. Genet. 41 (2009), 838–842.
29. Lauchle, J.O., Kim, D., Le, D.T., Akagi, K., Crone, M., Krisman, K., Warner, K., Bonifas, J.M., Li, Q., Coakley, K.M., et al. Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras. Nature 461 (2009), 411–414.
30. G12D from the endogenous locus. Blood 117 (2011), 2022–2032.
31. Li, Q., Bohin, N., Wen, T., Nr, V., Magee, J., Chen, S.C., Shannon, K., Morrison, S.J., Oncogenic Nras has bimodal effects on stem cells that sustainably increase competitiveness. Nature 504 (2013), 143–147.
32. Moran-Crusio, K., Reavie, L., Shih, A., Abdel-Wahab, O., Ndiaye-Lobry, D., Lobry, C., Figueroa, M.E., Vasanthakumar, A., Patel, J., Zhao, X., et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20 (2011), 11–24.
33. Murphy, T., Hori, S., Sewell, J., Gnanapragasam, V.J., Expression and functional role of negative signalling regulators in tumour development and progression. Int. J. Cancer 127 (2010), 2491–2499.
34. Nonami, A., Sattler, M., Weisberg, E., Liu, Q., Zhang, J., Patricelli, M.P., Christie, A.L., Saur, A.M., Kohl, N.E., Kung, A.L., et al. Identification of novel therapeutic targets in acute leukemias with NRAS mutations using a pharmacologic approach. Blood 125 (2015), 3133–3143.
35. Padron, E., Painter, J.S., Kunigal, S., Mailloux, A.W., McGraw, K., McDaniel, J.M., Kim, E., Bebbington, C., Baer, M., Yarranton, G., et al. GM-CSF-dependent pSTAT5 sensitivity is a feature with therapeutic potential in chronic myelomonocytic leukemia. Blood 121 (2013), 5068–5077.
36. Papaemmanuil, E., Gerstung, M., Bullinger, L., Gaidzik, V.I., Paschka, P., Roberts, N.D., Potter, N.E., Heuser, M., Thol, F., Bolli, N., et al. Genomic classification and prognosis in acute myeloid leukemia. N. Engl. J. Med. 374 (2016), 2209–2221.
37. Patel, J.P., Gönen, M., Figueroa, M.E., Fernandez, H., Sun, Z., Racevskis, J., Van Vilerverghe, P., Dolgalev, I., Thomas, S., Aminova, O., et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N. Engl. J. Med. 366 (2012), 1079–1089.
38. Pronier, E., Almire, C., Mokrani, H., Vasanthakumar, A., Simon, A., da Costa Reis Monte Mor, B., Massé, A., Le Couédic, J.P., Pendino, F., Carbonne, B., et al. Inhibition of TET2-mediated conversion of 5-methylcytosine to 5-hydroxymethylcytosine disturbs erythroid and granulomonocytic differentiation of human hematopoietic progenitors. Blood 118 (2011), 2551–2555.
39. Quentmeier, H., Reinhardt, J., Zaborski, M., Drexler, H.G., FLT3 mutations in acute myeloid leukemia cell lines. Leukemia 17 (2003), 120–124.
40. Quivoron, C., Couronné, L., Della Valle, V., Lopez, C.K., Plo, I., Wagner-Ballon, O., Do Cruzeiro, M., Delhommeau, F., Arnulf, B., Stern, M.H., et al. TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell 20 (2011), 25–38.
41. Schubbert, S., Shannon, K., Bollag, G., Hyperactive Ras in developmental disorders and cancer. Nat. Rev. Cancer 7 (2007), 295–308.
42. Shih, A.H., Jiang, Y., Meydan, C., Shank, K., Pandey, S., Barreyro, L., Antony-Debre, I., Viale, A., Socci, N., Sun, Y., et al. Mutational cooperativity linked to combinatorial epigenetic gain of function in acute myeloid leukemia. Cancer Cell 27 (2015), 502–515.
43. Shih, A.H., Meydan, C., Shank, K., Garrett-Bakelman, F.E., Ward, P.S., Intlekofer, A.M., Nazir, A., Stein, E.M., Knapp, K., Glass, J., et al. Combination targeted therapy to disrupt aberrant oncogenic signaling and reverse epigenetic dysfunction in IDH2- and TET2-mutant acute myeloid leukemia. Cancer Discov. 7 (2017), 494–505.
44. Tahiliani, M., Koh, K.P., Shen, Y., Pastor, W.A., Bandukwala, H., Brudno, Y., Agarwal, S., Iyer, L.M., Liu, D.R., Aravind, L., et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324 (2009), 930–935.
45. Waterston, R.H., Lindblad-Toh, K., Birney, E., Rogers, J., Abril, J.F., Agarwal, P., Agarwala, R., Ainscough, R., Alexandersson, M., An, P., et al. Initial sequencing and comparative analysis of the mouse genome. Nature 420 (2002), 520–562.
46. Xie, M., Lu, C., Wang, J., McLellan, M.D., Johnson, K.J., Wendl, M.C., McMichael, J.F., Schmidt, H.K., Yellapantula, V., Miller, C.A., et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat. Med. 20 (2014), 1472–1478.
47. G12D signaling to transform megakaryocyte-erythroid progenitors in acute myeloid leukemia. Blood 129 (2017), 358–370.
48. Zhao, Z., Chen, C.C., Rillahan, C.D., Shen, R., Kitzing, T., McNerney, M.E., Diaz-Flores, E., Zuber, J., Shannon, K., Le Beau, M.M., et al. Cooperative loss of RAS feedback regulation drives myeloid leukemogenesis. Nat. Genet. 47 (2015), 539–543.