An integrated approach to dissecting oncogene addiction implicates a Myb-coordinated self-renewal program as essential for leukemia maintenance

Genes and Development

Volumn 25, Issue 15, 2011, Pages 1628-1640

  Zuber, Johannes ^a,b   Rappaport, Amy R ^a,c   Luo, Weijun ^a   Wang, Eric ^a   Chen, Chong ^a   Vaseva, Angelina V ^a,d   Shi, Junwei ^a,d   Weissmueller, Susann ^a,c   Fellman, Christof ^a   Taylor, Meredith J ^a   Weissenboeck, Martina ^b   Graeber, Thomas G ^e   Kogan, Scott C ^f   Vakoc, Christopher R ^a   Lowe, Scott W ^a,c,g  

^a Howard Hughes Medical Institute Cold Spring Harbor Laboratory Cold Spring Harbor   (United States)

^b RESEARCH INSTITUTE OF MOLECULAR PATHOLOGY   (Austria)

^c WATSON SCHOOL OF BIOLOGICAL SCIENCES   (United States)

^d STONY BROOK UNIVERSITY   (United States)

^e UNIVERSITY OF CALIFORNIA   (United States)

^f UNIVERSITY OF CALIFORNIA   (United States)

^g HOWARD HUGHES MEDICAL INSTITUTE   (United States)

Author keywords

Aml; Mll af9; Mouse models; Myb; Oncogene addiction; Rnai; Smyd2

Indexed keywords

ONCOPROTEIN; ONCOPROTEIN MLL AF9; UNCLASSIFIED DRUG;

ACUTE GRANULOCYTIC LEUKEMIA; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; GENE TARGETING; GENETIC TRANSCRIPTION; MOUSE; MYELOPOIESIS; NONHUMAN; ONCOGEN ADDICTION; ONCOGENE; ONCOGENE MYB; PRIORITY JOURNAL; PROGNOSIS; RNA INTERFERENCE; STEM CELL;

ANIMALS; DISEASE MODELS, ANIMAL; GENE EXPRESSION REGULATION, NEOPLASTIC; GENES, MYB; HEMATOPOIESIS; LEUKEMIA; MICE; ONCOGENE PROTEINS, FUSION; ONCOGENES; PROTO-ONCOGENE PROTEINS C-MYB; RNA INTERFERENCE;

EID: 80051513341     PISSN: 08909369     EISSN: 15495477     Source Type: Journal    
DOI: 10.1101/gad.17269211     Document Type: Article

References (75)

1. Ayton PM, Cleary ML. 2003. Transformation of myeloid progenitors by MLL oncoproteins is dependent on Hoxa7 and Hoxa9. Genes Dev. 17: 2298-2307.
2. Bender TP, Kremer CS, Kraus M, Buch T, Rajewsky K. 2004. Critical functions for c-Myb at three checkpoints during thymocyte development. Nat Immunol 5: 721-729.
3. Chandra P, Luthra R, Zuo Z, Yao H, Ravandi F, Reddy N, Garcia-Manero G, Kantarjian H, Jones D. 2010. Acute myeloid leukemia with t(9;11)(p21-22;q23): common properties of dysregulated ras pathway signaling and genomic progression characterize de novo and therapy-related cases. Am J Clin Pathol 133: 686-693.
4. Chin L, Tam A, Pomerantz J, Wong M, Holash J, Bardeesy N, Shen Q, O'Hagan R, Pantginis J, Zhou H, et al. 1999. Essential role for oncogenic Ras in tumour maintenance. Nature 400: 468-472.
5. Chonghaile TN, Letai A. 2008. Mimicking the BH3 domain to kill cancer cells. Oncogene 27: S149-S157. doi: 10.1038/ onc.2009.52
6. Clappier E, Cuccuini W, Kalota A, Crinquette A, Cayuela JM, Dik WA, Langerak AW, Montpellier B, Nadel B, Walrafen P, et al. 2007. The C-MYB locus is involved in chromosomal translocation and genomic duplications in human T-cell acute leukemia (T-ALL), the translocation defining a new T-ALL subtype in very young children. Blood 110: 1251-1261.
7. Cozzio A, Passegue E, Ayton PM, Karsunky H, Cleary ML, Weissman IL. 2003. Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes Dev 17: 3029-3035.
8. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, et al. 2001. Efficacy and safety of a specific inhibitor of the BCRABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344: 1031-1037.
9. Ehrenreiter K, Kern F, Velamoor V, Meissl K, Galabova-Kovacs G, Sibilia M, Baccarini M. 2009. Raf-1 addiction in Rasinduced skin carcinogenesis. Cancer Cell 16: 149-160.
10. Emambokus N, Vegiopoulos A, Harman B, Jenkinson E, Anderson G, Frampton J. 2003. Progression through key stages of haemopoiesis is dependent on distinct threshold levels of c-Myb. EMBO J 22: 4478-4488.
11. Ernst P, Fisher JK, Avery W, Wade S, Foy D, Korsmeyer SJ. 2004. Definitive hematopoiesis requires the mixed-lineage leukemia gene. Dev. Cell 6: 437-443.
12. Estey E, Dohner H. 2006. Acute myeloid leukaemia. Lancet 368: 1894-1907.
13. Evans JL, Moore TL, Kuehl WM, Bender T, Ting JP. 1990. Functional analysis of c-Myb protein in T-lymphocytic cell lines shows that it trans-activates the c-myc promoter. Mol Cell Biol 10: 5747-5752.
14. Fahl S, Crittenden R, Allman D, Bender T. 2009. c-Myb is required for pro-B cell differentiation. J Immunol 183: 5582-5592.
15. Fellmann C, Zuber J, McJunkin K, Chang K, Malone CD, Dickins RA, Xu Q, Hengartner MO, Elledge SJ, Hannon GJ, et al. 2011. Functional identification of optimized RNAi triggers using a massively parallel sensor assay. Mol Cell 41: 733-746.
16. Felsher DW, Bishop JM. 1999. Reversible tumorigenesis by MYC in hematopoietic lineages. Mol Cell 4: 199-207.
17. Galderisi U, Cipollaro M, Giordano A. 2006. The retinoblastoma gene is involved in multiple aspects of stem cell biology. Oncogene 25: 5250-5256.
18. Gunther EJ, Moody SE, Belka GK, Hahn KT, Innocent N, Dugan KD, Cardiff RD, Chodosh LA. 2003. Impact of p53 loss on reversal and recurrence of conditional Wnt-induced tumorigenesis. Genes Dev 17: 488-501.
19. Hess JL, Bittner CB, Zeisig DT, Bach C, Fuchs U, Borkhardt A, Frampton J, Slany RK. 2006. c-Myb is an essential downstream target for homeobox-mediated transformation of hematopoietic cells. Blood 108: 297-304.
20. Hoelbl A, Schuster C, Kovacic B, Zhu B, Wickre M, Hoelzl MA, Fajmann S, Grebien F, Warsch W, Stengl G, et al. 2010. Stat5 is indispensable for the maintenance of bcr/abl-positive leukaemia. EMBO Mol Med 2: 98-110.
21. Horton SJ, Walf-Vorderwulbecke V, Chatters SJ, Sebire NJ, de Boer J, Williams O. 2008. Acute myeloid leukemia induced by MLL-ENL is cured by oncogene ablation despite acquisition of complex genetic abnormalities. Blood 113: 4922-4929.
22. Huang J, Perez-Burgos L, Placek BJ, Sengupta R, Richter M, Dorsey JA, Kubicek S, Opravil S, Jenuwein T, Berger SL. 2006. Repression of p53 activity by Smyd2-mediated methylation. Nature 444: 629-632.
23. Jin S, Zhao H, Yi Y, Nakata Y, Kalota A, Gewirtz AM. 2010. c-Myb binds MLL through menin in human leukemia cells and is an important driver of MLL-associated leukemogenesis. J Clin Invest 120: 593-606.
24. Kim J, Woo AJ, Chu J, Snow JW, Fujiwara Y, Kim CG, Cantor AB, Orkin SH. 2010. A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs. Cell 143: 313-324.
25. Klempnauer KH, Bishop JM. 1984. Neoplastic transformation by E26 leukemia virus is mediated by a single protein containing domains of gag and myb genes. J Virol 50: 280-283.
26. Komatsu S, Imoto I, Tsuda H, Kozaki KI, Muramatsu T, Shimada Y, Aiko S, Yoshizumi Y, Ichikawa D, Otsuji E, et al. 2009. Overexpression of SMYD2 relates to tumor cell proliferation and malignant outcome of esophageal squamous cell carcinoma. Carcinogenesis 30: 1139-1146.
27. Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S, Deng X, Zhai D, Shi YX, Sneed T, et al. 2006. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 10: 375-388.
28. Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang Y, Faber J, Levine JE, Wang J, Hahn WC, Gilliland DG, et al. 2006. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 442: 818-822.
29. Liang DC, Shih LY, Fu JF, Li HY, Wang HI, Hung IJ, Yang CP, Jaing TH, Chen SH, Liu HC. 2006. K-Ras mutations and N-Ras mutations in childhood acute leukemias with or without mixed-lineage leukemia gene rearrangements. Cancer 106: 950-956.
30. Lieu YK, Reddy EP. 2009. Conditional c-myb knockout in adult hematopoietic stem cells leads to loss of self-renewal due to impaired proliferation and accelerated differentiation. Proc Natl Acad Sci 106: 21689-21694.
31. Lin C, Smith ER, Takahashi H, Lai KC, Martin-Brown S, Florens L, Washburn MP, Conaway JW, Conaway RC, Shilatifard A. 2010. AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. Mol Cell 37: 429-437.
32. Luger SM, O'Brien SG, Ratajczak J, Ratajczak MZ, Mick R, Stadtmauer EA, Nowell PC, Goldman JM, Gewirtz AM. 2002. Oligodeoxynucleotide-mediated inhibition of c-myb gene expression in autografted bone marrow: a pilot study. Blood 99: 1150-1158.
33. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, et al. 2004. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350: 2129-2139.
34. Malaterre J, Carpinelli M, Ernst M, Alexander W, Cooke M, Sutton S, Dworkin S, Heath JK, Frampton J, McArthur G, et al. 2007. c-Myb is required for progenitor cell homeostasis in colonic crypts. Proc Natl Acad Sci 104: 3829-3834.
35. McJunkin K, Mazurek A, Premsrirut PK, Zuber J, Dow LE, Simon J, Stillman B, Lowe SW. 2011. Reversible suppression of an essential gene in adult mice using transgenic RNA interference. Proc Natl Acad Sci 108: 7113-7118.
36. Metzeler KH, Hummel M, Bloomfield CD, Spiekermann K, Braess J, Sauerland MC, Heinecke A, Radmacher M, Marcucci G, Whitman SP, et al. 2008. An 86-probe-set gene-expression signature predicts survival in cytogenetically normal acute myeloid leukemia. Blood 112: 4193-4201.
37. Milyavsky M, Gan OI, Trottier M, Komosa M, Tabach O, Notta F, Lechman E, Hermans KG, Eppert K, Konovalova Z, et al. 2010. A distinctive DNA damage response in human hematopoietic stem cells reveals an apoptosis-independent role for p53 in self-renewal. Cell Stem Cell 7: 186-197.
38. Mucenski ML, McLain K, Kier AB, Swerdlow SH, Schreiner CM, Miller TA, Pietryga DW, Scott WJ, Potter SS. 1991. A functional c-myb gene is required for normal murine fetal hepatic hematopoiesis. Cell 65: 677-689.
39. Naoe T, Kubo K, Kiyoi H, Ohno R, Akao Y, Yoshida J, Kato K, Kojima S, Matsuyama T. 1993. Involvement of the MLL/ ALL-1 gene associated with multiple point mutations of the N-ras gene in acute myeloid leukemia with t(11;17)(q23;q25). Blood 82: 2260-2261.
40. Neubauer A, Maharry K, Mrozek K, Thiede C, Marcucci G, Paschka P, Mayer RJ, Larson RA, Liu ET, Bloomfield CD. 2008. Patients with acute myeloid leukemia and RAS mutations benefit most from postremission high-dose cytarabine: a cancer and leukemia group B study. J Clin Oncol 26: 4603-4609.
41. Nomura N, Takahashi M, Matsui M, Ishii S, Date T, Sasamoto S, Ishizaki R. 1988. Isolation of human cDNA clones of mybrelated genes, A-myb and B-myb. Nucleic Acids Res 16: 11075-11089.
42. Okada Y, Feng Q, Lin Y, Jiang Q, Li Y, Coffield VM, Su L, Xu G, Zhang Y. 2005. hDOT1L links histone methylation to leukemogenesis. Cell 121: 167-178.
43. Ono R, Nakajima H, Ozaki K, Kumagai H, Kawashima T, Taki T, Kitamura T, Hayashi Y, Nosaka T. 2005. Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple-lineage leukemogenesis. J Clin Invest 115: 919-929.
44. Pan G, Thomson JA. 2007. Nanog and transcriptional networks in embryonic stem cell pluripotency. Cell Res 17: 42-49.
45. Pardee TS, Zuber J, Lowe SW. 2011. Flt3-ITD alters chemotherapy response in vitro and in vivo in a p53-dependent manner. Exp Hematol 39: 473-485.
46. Persson M, Andren Y, Mark J, Horlings HM, Persson F, Stenman G. 2009. Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck. Proc Natl Acad Sci 106: 18740-18744.
47. Plaisier SB, Taschereau R, Wong JA, Graeber TG. 2010. Rankrank hypergeometric overlap: identification of statistically significant overlap between gene-expression signatures. Nucleic Acids Res 38: e169. doi: 10.1093/nar/gkq636
48. Politi K, Zakowski MF, Fan PD, Schonfeld EA, Pao W, Varmus HE. 2006. Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors. Genes Dev 20: 1496-1510.
49. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. 2010. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464: 427-430.
50. Pratilas CA, Solit DB. 2010. Targeting the mitogen-activated protein kinase pathway: physiological feedback and drug response. Clin Cancer Res 16: 3329-3334.
51. Radtke I, Mullighan CG, Ishii M, Su X, Cheng J, Ma J, Ganti R, Cai Z, Goorha S, Pounds SB, et al. 2009. Genomic analysis reveals few genetic alterations in pediatric acute myeloid leukemia. Proc Natl Acad Sci 106: 12944-12949.
52. Ramsay RG, Gonda TJ. 2008. MYB function in normal and cancer cells. Nat Rev Cancer 8: 523-534.
53. Ratajczak MZ, Hijiya N, Catani L, DeRiel K, Luger SM, McGlave P, Gewirtz AM. 1992. Acute-and chronic-phase chronic myelogenous leukemia colony-forming units are highly sensitive to the growth inhibitory effects of c-myb antisense oligodeoxynucleotides. Blood 79: 1956-1961.
54. Rosenbauer F, Tenen DG. 2007. Transcription factors in myeloid development: balancing differentiation with transformation. Nat Rev Immunol 7: 105-117.
55. Saddic LA, West LE, Aslanian A, Yates JR 3rd, Rubin SM, Gozani O, Sage J. 2010. Methylation of the retinoblastoma tumor suppressor by SMYD2. J Biol Chem285: 37733-37740.
56. Schoch C, Schnittger S, Klaus M, Kern W, Hiddemann W, Haferlach T. 2003. AML with 11q23/MLL abnormalities as defined by the WHO classification: incidence, partner chromosomes, FAB subtype, age distribution, and prognostic impact in an unselected series of 1897 cytogenetically analyzed AML cases. Blood 102: 2395-2402.
57. Shen-Ong GL, Morse HC 3rd, Potter M, Mushinski JF. 1986. Two modes of c-myb activation in virus-induced mouse myeloid tumors. Mol Cell Biol 6: 380-392.
58. Smith KN, Singh AM, Dalton S. 2010. Myc represses primitive endoderm differentiation in pluripotent stem cells. Cell Stem Cell 7: 343-354.
59. Somervaille TC, Matheny CJ, Spencer GJ, Iwasaki M, Rinn JL, Witten DM, Chang HY, Shurtleff SA, Downing JR, Cleary ML. 2009. Hierarchical maintenance of MLL myeloid leukemia stem cells employs a transcriptional program shared with embryonic rather than adult stem cells. Cell StemCell 4: 129-140.
60. Soucek L, Whitfield J, Martins CP, Finch AJ, Murphy DJ, Sodir NM, Karnezis AN, Swigart LB, Nasi S, Evan GI. 2008. Modelling Myc inhibition as a cancer therapy. Nature 455: 679-683.
61. Spannhoff A, Hauser AT, Heinke R, Sippl W, Jung M. 2009. The emerging therapeutic potential of histone methyltransferase and demethylase inhibitors. ChemMedChem 4: 1568-1582.
62. Steger DJ, Lefterova MI, Ying L, Stonestrom AJ, Schupp M, Zhuo D, Vakoc AL, Kim JE, Chen J, Lazar MA, et al. 2008. DOT1L/ KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells. Mol Cell Biol 28: 2825-2839.
63. Stubbs MC, Kim YM, Krivtsov AV, Wright RD, Feng Z, Agarwal J, Kung AL, Armstrong SA. 2008. MLL-AF9 and FLT3 cooperation in acute myelogenous leukemia: development of a model for rapid therapeutic assessment. Leukemia 22: 66-77.
64. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, et al. 2005. Gene set enrichment analysis: a knowledgebased approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci 102: 15545-15550.
65. Weinstein IB. 2002. Cancer. Addiction to oncogenes-the Achilles heal of cancer. Science 297: 63-64.
66. Weinstein IB, Joe AK. 2006. Mechanisms of disease: oncogene addiction-a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol 3: 448-457.
67. Wong P, Iwasaki M, Somervaille TC, So CW, So CW, Cleary ML. 2007. Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential. Genes Dev. 21: 2762-2774.
68. Yagi T, Morimoto A, Eguchi M, Hibi S, Sako M, Ishii E, Mizutani S, Imashuku S, Ohki M, Ichikawa H. 2003. Identification of a gene expression signature associated with pediatric AML prognosis. Blood 102: 1849-1856.
69. Yokoyama A, Lin M, Naresh A, Kitabayashi I, Cleary ML. 2010. A higher-order complex containing AF4 and ENL family proteins with P-TEFb facilitates oncogenic and physiologic MLL-dependent transcription. Cancer Cell 17: 198-212.
70. Young RA. 2011. Control of the embryonic stem cell state. Cell 144: 940-954.
71. Zeisig BB, Milne T, Garcia-Cuellar MP, Schreiner S, Martin ME, Fuchs U, Borkhardt A, Chanda SK, Walker J, Soden R, et al. 2004. Hoxa9 and Meis1 are key targets for MLL-ENL-mediated cellular immortalization. Mol Cell Biol 24: 617-628.
72. Zhao Z, Zuber J, Diaz-Flores E, Lintault L, Kogan SC, Shannon K, Lowe SW. 2010. p53 loss promotes acute myeloid leukemia by enabling aberrant self-renewal. Genes Dev 24: 1389-1402.
73. Zuber J, Radtke I, Pardee TS, Zhao Z, Rappaport AR, Luo W, McCurrach ME, Yang MM, Dolan ME, Kogan SC, et al. 2009. Mouse models of human AML accurately predict chemotherapy response. Genes Dev 23: 877-889.
74. Zuber J, McJunkin K, Fellmann C, Dow LE, Taylor MJ, Hannon GJ, Lowe SW. 2011a. Toolkit for evaluating genes required for proliferation and survival using tetracycline-regulated RNAi. Nat Biotechnol 29: 79-83.
75. Zuber J, Shi J, Wang E, Rappaport AR, Herrmann H, Sison EA, Magoon D, Qi J, Blatt K, Wunderlich M, et al. 2011b. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukemia. Nature. doi: 10.1038/nature10334.