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Acute Leukemias

New insights into MLL gene rearranged acute leukemias using gene expression profiling: shared pathways, lineage commitment, and partner genes

Leukemia volume 19, pages 953–964 (2005)Cite this article

Abstract

Rearrangements of the MLL gene occur in both acute lymphoblastic and acute myeloid leukemias (ALL, AML). This study addressed the global gene expression pattern of these two leukemia subtypes with respect to common deregulated pathways and lineage-associated differences. We analyzed 73 t(11q23)/MLL leukemias in comparison to 290 other acute leukemias and demonstrate that 11q23 leukemias combined are characterized by a common specific gene expression signature. Additionally, in unsupervised and supervised data analysis algorithms, ALL and AML cases with t(11q23) segregate according to the lineage they are derived from, that is, myeloid or lymphoid, respectively. This segregation can be explained by a highly differing transcriptional program. Through the use of novel biological network analyses, essential regulators of early B cell development, PAX5 and EBF, were shown to be associated with a clear B-lineage commitment in lymphoblastic t(11q23)/MLL leukemias. Also, the influence of the different MLL translocation partners on the transcriptional program was directly assessed. Interestingly, gene expression profiling did not reveal a clear distinct pattern associated with one of the analyzed partner genes. Taken together, the identified molecular expression pattern of MLL fusion gene samples and biological networks revealed new insights into the aberrant transcriptional program in 11q23/MLL leukemias.

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References

  1. Biondi A, Cimino G, Pieters R, Pui CH . Biological and therapeutic aspects of infant leukemia. Blood 2000; 96: 24–33.

    CAS  PubMed  Google Scholar 

  2. Pui CH, Relling MV, Downing JR . Acute lymphoblastic leukemia. N Engl J Med 2004; 350: 1535–1548.

    Article  CAS  PubMed  Google Scholar 

  3. Schoch C, Schnittger S, Klaus M, Kern W, Hiddemann W, Haferlach T . 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 2003; 102: 2395–2402.

    Article  CAS  PubMed  Google Scholar 

  4. Huret JL, Dessen P, Bernheim A . An atlas of chromosomes in hematological malignancies. Example: 11q23 and MLL partners. Leukemia 2001; 15: 987–989.

    Article  CAS  PubMed  Google Scholar 

  5. Schnittger S, Kinkelin U, Schoch C, Heinecke A, Haase D, Haferlach T et al. Screening for MLL tandem duplication in 387 unselected patients with AML identify a prognostically unfavorable subset of AML. Leukemia 2000; 14: 796–804.

    Article  CAS  PubMed  Google Scholar 

  6. Ernst P, Wang J, Korsmeyer SJ . The role of MLL in hematopoiesis and leukemia. Curr Opin Hematol 2002; 9: 282–287.

    Article  PubMed  Google Scholar 

  7. Ayton PM, Cleary ML . Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins. Oncogene 2001; 20: 5695–5707.

    Article  CAS  PubMed  Google Scholar 

  8. So CW, Cleary ML . Dimerization: a versatile switch for oncogenesis. Blood 2004; 104: 919–921.

    Article  CAS  PubMed  Google Scholar 

  9. Collins EC, Rabbitts TH . The promiscuous MLL gene links chromosomal translocations to cellular differentiation and tumour tropism. Trends Mol Med 2002; 8: 436–442.

    Article  CAS  PubMed  Google Scholar 

  10. Lipshutz RJ, Fodor SP, Gingeras TR, Lockhart DJ . High density synthetic oligonucleotide arrays. Nat Genet 1999; 21: 20–24.

    Article  CAS  PubMed  Google Scholar 

  11. Slonim DK . From patterns to pathways: gene expression data analysis comes of age. Nat Genet 2002; 32 (Suppl.): 502–508.

    Article  CAS  PubMed  Google Scholar 

  12. Dugas M, Schoch C, Schnittger S, Haferlach T, Danhauser-Riedl S, Hiddemann W et al. A comprehensive leukemia database: integration of cytogenetics, molecular genetics and microarray data with clinical information, cytomorphology and immunophenotyping. Leukemia 2001; 15: 1805–1810.

    Article  CAS  PubMed  Google Scholar 

  13. Kern W, Kohlmann A, Wuchter C, Schnittger S, Schoch C, Mergenthaler S et al. Correlation of protein expression and gene expression in acute leukemia. Cytometry 2003; 55B: 29–36.

    Article  CAS  Google Scholar 

  14. Kohlmann A, Schoch C, Schnittger S, Dugas M, Hiddemann W, Kern W et al. Molecular characterization of acute leukemias by use of microarray technology. Genes Chromosomes Cancer 2003; 37: 396–405.

    Article  CAS  PubMed  Google Scholar 

  15. Kohlmann A, Schoch C, Schnittger S, Dugas M, Hiddemann W, Kern W et al. Pediatric acute lymphoblastic leukemia (ALL) gene expression signatures classify an independent cohort of adult ALL patients. Leukemia 2004; 18: 63–71.

    Article  CAS  PubMed  Google Scholar 

  16. Schoch C, Kohlmann A, Schnittger S, Brors B, Dugas M, Mergenthaler S et al. Acute myeloid leukemias with reciprocal rearrangements can be distinguished by specific gene expression profiles. Proc Natl Acad Sci USA 2002; 99: 10008–10013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yeang CH, Ramaswamy S, Tamayo P, Mukherjee S, Rifkin RM, Angelo M et al. Molecular classification of multiple tumor types. Bioinformatics 2001; 17 (Suppl 1): S316–S322.

    Article  PubMed  Google Scholar 

  18. Storey JD, Tibshirani R . Statistical significance for genomewide studies. Proc Natl Acad Sci USA 2003; 100: 9440–9445.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Vapnik V . Statistical Learning Theory. New York: Wiley, 1998.

    Google Scholar 

  20. Furey TS, Cristianini N, Duffy N, Bednarski DW, Schummer M, Haussler D . Support vector machine classification and validation of cancer tissue samples using microarray expression data. Bioinformatics 2000; 16: 906–914.

    Article  CAS  PubMed  Google Scholar 

  21. Brown MP, Grundy WN, Lin D, Cristianini N, Sugnet CW, Furey TS et al. Knowledge-based analysis of microarray gene expression data by using support vector machines. Proc Natl Acad Sci USA 2000; 97: 262–267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tusher VG, Tibshirani R, Chu G . Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 2001; 98: 5116–5121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ebert BL, Golub TR . Genomic approaches to hematologic malignancies. Blood 2004; 104: 923–932.

    Article  CAS  PubMed  Google Scholar 

  24. Grimwade D, Haferlach T . Gene-expression profiling in acute myeloid leukemia. N Engl J Med 2004; 350: 1676–1678.

    Article  CAS  PubMed  Google Scholar 

  25. Haferlach T, Kohlmann A, Kern W, Hiddemann W, Schnittger S, Schoch C . Gene expression profiling as a tool for the diagnosis of acute leukemias. Semin Hematol 2003; 40: 281–295.

    Article  CAS  PubMed  Google Scholar 

  26. Armstrong SA, Staunton JE, Silverman LB, Pieters R, Den Boer ML, Minden MD et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet 2002; 30: 41–47.

    Article  CAS  PubMed  Google Scholar 

  27. Bullinger L, Dohner K, Bair E, Frohling S, Schlenk RF, Tibshirani R et al. Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. N Engl J Med 2004; 350: 1605–1616.

    Article  CAS  PubMed  Google Scholar 

  28. Ross ME, Zhou X, Song G, Shurtleff SA, Girtman K, Williams WK et al. Classification of pediatric acute lymphoblastic leukemia by gene expression profiling. Blood 2003; 102: 2951–2959.

    Article  CAS  PubMed  Google Scholar 

  29. Ross ME, Mahfouz R, Onciu M, Liu HC, Zhou X, Song G et al. Gene expression profiling of pediatric acute myelogenous leukemia. Blood 2004; 104: 3679–3687.

    Article  CAS  PubMed  Google Scholar 

  30. Rozovskaia T, Ravid-Amir O, Tillib S, Getz G, Feinstein E, Agrawal H et al. Expression profiles of acute lymphoblastic and myeloblastic leukemias with ALL-1 rearrangements. Proc Natl Acad Sci USA 2003; 100: 7853–7858.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Valk PJ, Verhaak RG, Beijen MA, Erpelinck CA, Barjesteh van Waalwijk van Doorn-Khosrovani, Boer JM et al. Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med 2004; 350: 1617–1628.

    Article  CAS  PubMed  Google Scholar 

  32. Yeoh EJ, Ross ME, Shurtleff SA, Williams WK, Patel D, Mahfouz R et al. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell 2002; 1: 133–143.

    Article  CAS  PubMed  Google Scholar 

  33. Kumar AR, Hudson WA, Chen W, Nishiuchi R, Yao Q, Kersey JH . Hoxa9 influences the phenotype but not the incidence of Mll-AF9 fusion gene leukemia. Blood 2004; 103: 1823–1828.

    Article  CAS  PubMed  Google Scholar 

  34. Rozovskaia T, Feinstein E, Mor O, Foa R, Blechman J, Nakamura T et al. Upregulation of Meis1 and HoxA9 in acute lymphocytic leukemias with the t(4:11) abnormality. Oncogene 2001; 20: 874–878.

    Article  CAS  PubMed  Google Scholar 

  35. Thorsteinsdottir U, Kroon E, Jerome L, Blasi F, Sauvageau G . Defining roles for HOX and MEIS1 genes in induction of acute myeloid leukemia. Mol Cell Biol 2001; 21: 224–234.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ito Y . Oncogenic potential of the RUNX gene family: ‘overview’. Oncogene 2004; 23: 4198–4208.

    Article  CAS  PubMed  Google Scholar 

  37. Stewart M, Terry A, Hu M, O'Hara M, Blyth K, Baxter E et al. Proviral insertions induce the expression of bone-specific isoforms of PEBP2alphaA (CBFA1): evidence for a new myc collaborating oncogene. Proc Natl Acad Sci USA 1997; 94: 8646–8651.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hyun TS, Ross TS . HIP1: trafficking roles and regulation of tumorigenesis. Trends Mol Med 2004; 10: 194–199.

    Article  CAS  PubMed  Google Scholar 

  39. Saitoh T, Mine T, Katoh M . Molecular cloning and expression of proto-oncogene FRAT1 in human cancer. Int J Oncol 2002; 20: 785–789.

    CAS  PubMed  Google Scholar 

  40. Kim NG, Rhee H, Li LS, Kim H, Lee JS, Kim JH et al. Identification of MARCKS, FLJ11383 and TAF1B as putative novel target genes in colorectal carcinomas with microsatellite instability. Oncogene 2002; 21: 5081–5087.

    Article  CAS  PubMed  Google Scholar 

  41. Miyoshi A, Kitajima Y, Sumi K, Sato K, Hagiwara A, Koga Y et al. Snail and SIP1 increase cancer invasion by upregulating MMP family in hepatocellular carcinoma cells. Br J Cancer 2004; 90: 1265–1273.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Almasan A, Ashkenazi A . Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy. Cytokine Growth Factor Rev 2003; 14: 337–348.

    Article  CAS  PubMed  Google Scholar 

  43. ten Dijke P, Goumans MJ, Itoh F, Itoh S . Regulation of cell proliferation by Smad proteins. J Cell Physiol 2002; 191: 1–16.

    Article  CAS  PubMed  Google Scholar 

  44. Gilliland DG, Griffin JD . The roles of FLT3 in hematopoiesis and leukemia. Blood 2002; 100: 1532–1542.

    Article  CAS  PubMed  Google Scholar 

  45. Armstrong SA, Kung AL, Mabon ME, Silverman LB, Stam RW, Den Boer ML et al. Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification. Cancer Cell 2003; 3: 173–183.

    Article  CAS  PubMed  Google Scholar 

  46. Busslinger M . Transcriptional control of early B cell development1. Annu Rev Immunol 2004; 22: 55–79.

    Article  CAS  PubMed  Google Scholar 

  47. Maier H, Hagman J . Roles of EBF and Pax-5 in B lineage commitment and development. Semin Immunol 2002; 14: 415–422.

    Article  CAS  PubMed  Google Scholar 

  48. Pirrotta V . Polycombing the genome: PcG, trxG, and chromatin silencing. Cell 1998; 93: 333–336.

    Article  CAS  PubMed  Google Scholar 

  49. Satijn DP, Olson DJ, van der Vlag J, Hamer KM, Lambrechts C, Masselink H et al. Interference with the expression of a novel human polycomb protein, hPc2, results in cellular transformation and apoptosis. Mol Cell Biol 1997; 17: 6076–6086.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kummalue T, Friedman AD . Cross-talk between regulators of myeloid development: C/EBPalpha binds and activates the promoter of the PU.1 gene. J Leukoc Biol 2003; 74: 464–470.

    Article  CAS  PubMed  Google Scholar 

  51. Richards MK, Liu F, Iwasaki H, Akashi K, Link DC . Pivotal role of granulocyte colony-stimulating factor in the development of progenitors in the common myeloid pathway. Blood 2003; 102: 3562–3568.

    Article  CAS  PubMed  Google Scholar 

  52. Iwasaki-Arai J, Iwasaki H, Miyamoto T, Watanabe S, Akashi K . Enforced granulocyte/macrophage colony-stimulating factor signals do not support lymphopoiesis, but instruct lymphoid to myelomonocytic lineage conversion. J Exp Med 2003; 197: 1311–1322.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sangrar W, Gao Y, Zirngibl RA, Scott ML, Greer PA . The fps/fes proto-oncogene regulates hematopoietic lineage output. Exp Hematol 2003; 31: 1259–1267.

    Article  CAS  PubMed  Google Scholar 

  54. Kim J, Ogata Y, Feldman RA . Fes tyrosine kinase promotes survival and terminal granulocyte differentiation of factor-dependent myeloid progenitors (32D) and activates lineage-specific transcription factors. J Biol Chem 2003; 278: 14978–14984.

    Article  CAS  PubMed  Google Scholar 

  55. Cousar JB, Briggs RC . Expression of human myeloid cell nuclear differentiation antigen (MNDA) in acute leukemias. Leuk Res 1990; 14: 915–920.

    Article  CAS  PubMed  Google Scholar 

  56. Asefa B, Klarmann KD, Copeland NG, Gilbert DJ, Jenkins NA, Keller JR . The interferon-inducible p200 family of proteins: a perspective on their roles in cell cycle regulation and differentiation. Blood Cells Mol Dis 2004; 32: 155–167.

    Article  CAS  PubMed  Google Scholar 

  57. Braganca J, Swingler T, Marques FI, Jones T, Eloranta JJ, Hurst HC et al. Human CREB-binding protein/p300-interacting transactivator with ED-rich tail (CITED) 4, a new member of the CITED family, functions as a co-activator for transcription factor AP-2. J Biol Chem 2002; 277: 8559–8565.

    Article  CAS  PubMed  Google Scholar 

  58. Yahata T, Takedatsu H, Dunwoodie SL, Braganca J, Swingler T, Withington SL et al. Cloning of mouse Cited4, a member of the CITED family p300/CBP-binding transcriptional coactivators: induced expression in mammary epithelial cells. Genomics 2002; 80: 601–613.

    Article  CAS  PubMed  Google Scholar 

  59. Cozzio A, Passegue E, Ayton PM, Karsunky H, Cleary ML, Weissman IL . Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes Dev 2003; 17: 3029–3035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Rubnitz JE, Morrissey J, Savage PA, Cleary ML . ENL, the gene fused with HRX in t(11;19) leukemias, encodes a nuclear protein with transcriptional activation potential in lymphoid and myeloid cells. Blood 1994; 84: 1747–1752.

    CAS  PubMed  Google Scholar 

  61. Zeisig BB, Milne T, Garcia-Cuellar MP, Schreiner S, Martin ME, Fuchs U et al. Hoxa9 and Meis1 are key targets for MLL-ENL-mediated cellular immortalization. Mol Cell Biol 2004; 24: 617–628.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. So CW, Karsunky H, Passegue E, Cozzio A, Weissman IL, Cleary ML . MLL-GAS7 transforms multipotent hematopoietic progenitors and induces mixed lineage leukemias in mice. Cancer Cell 2003; 3: 161–171.

    Article  CAS  PubMed  Google Scholar 

  63. Jaffe ES, Harris NL, Stein H, Vardiman JW . World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, IARC Press, 2001.

    Google Scholar 

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Acknowledgements

We thank Sonja Rauhut for excellent technical assistance and Dr Sylvia Merk for help with unsupervised data analyses. This study is supported in part by German José Carreras Foundation; Grant Number: DJCS-R00/13; Roche Diagnostics GmbH, ICCU, Penzberg, Germany (all to TH).

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Authors and Affiliations

  1. Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, Ludwig-Maximilians University, Munich, Germany

    A Kohlmann, C Schoch, S Schnittger, W Hiddemann, W Kern & T Haferlach

  2. Department of Medical Informatics, Biometrics and Epidemiology, Ludwig-Maximilians University, Munich, Germany

    M Dugas

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  1. A Kohlmann
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Correspondence to A Kohlmann.

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Kohlmann, A., Schoch, C., Dugas, M. et al. New insights into MLL gene rearranged acute leukemias using gene expression profiling: shared pathways, lineage commitment, and partner genes. Leukemia 19, 953–964 (2005). https://doi.org/10.1038/sj.leu.2403746

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