Expression analyses identify MLL as a prominent target of 11q23 amplification and support an etiologic role for MLL gain of function in myeloid malignancies
[en] MLL amplification was recently recognized as a recurrent aberration in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), associated with adverse prognosis and karyotype complexity. Here we present detailed results of fluorescence in situ hybridization (FISH) and expression analyses of MLL and 5 selected 11q candidate oncogenes (CBL, DDX6, ETS1, FLI1, and PLZF) in 31 patient samples and one cell line with 11q23 gain. FISH analyses revealed that the 11q23 amplicon invariably encompassed MLL, DDX6, ETS1, and FLI1, whereas expression analyses identified MLL and DDX6 as the most differentially expressed genes among samples with and without 11q23 copy gain or amplification. In MLL-amplified samples, a significant transcriptional up-regulation of MEIS1, PROML1, ADAM10, NKG2D, and ITPA was noted. Further analyses, designed to elucidate a possible role of the 11q overexpressed genes (MLL, DDX6, FLI1, and ETS1) in unselected MDS and AML samples, revealed a significant upregulation of MLL in MDS. Our findings confirm the MLL gene as a prominent target of 11q23 amplification and provide further evidence for an etiologic role for MLL gain of function in myeloid malignancies. In addition, our results indicate that the transcriptional program associated with MLL rearrangements and MLL overexpression displays significant similarities.
Disciplines :
Hematology
Author, co-author :
Poppe, B.
Vandesompele, J.
Schoch, C.
Lindvall, C.
Mrozek, K.
Bloomfield, C. D.
Beverloo, H. B.
Michaux, L.
Dastugue, N.
Herens, Christian ; Centre Hospitalier Universitaire de Liège - CHU > PLAN COS
Expression analyses identify MLL as a prominent target of 11q23 amplification and support an etiologic role for MLL gain of function in myeloid malignancies
Publication date :
01 January 2004
Journal title :
Blood
ISSN :
0006-4971
eISSN :
1528-0020
Publisher :
Amer Soc Hematology, Washington, United States - Washington
Schwab M. Oncogene amplification in solid tumors. Semin Cancer Biol. 1999;9:319-325.
Andersen MK, Christiansen DH, Kirchhoff M, Pedersen-Bjergaard J. Duplication or amplification of chromosome band 11q23, including the unrearranged MLL gene, is a recurrent abnormality in therapy-related MDS and AML, and is closely related to mutation of the TP53 gene and to previous therapy with alkylating agents. Genes Chromosomes Cancer. 2001;31:33-41.
Andreasson P, Johansson B, Billström R, Garwicz S, Mitelman F, Höglund M. Fluorescence in situ hybridization analyses of hematologic malignancies reveal frequent cytogenetically unrecognized 12p rearrangements. Leukemia. 1998;12:390-400.
Fonatsch C, Nowotny H, Pittermann-Höcker E, et al. Amplification of ribosomal RNA genes in acute myeloid leukemia. Genes Chromosomes Cancer. 2001;32:11-17.
Michaux L, Wlodarska I, Stul M, et al. MLL amplification in myeloid leukemias: a study of 14 cases with multiple copies of 11q23. Genes Chromosomes Cancer. 2000;29:40-47.
Streubel B, Valent P, Lechner K, Fonatsch C. Amplification of the AML 1(CBFA2) gene on ring chromosomes in a patient with acute myeloid leukemia and a constitutional ring chromosome 21. Cancer Genet Cytogenet. 2001;124:42-46.
Van Limbergen H, Poppe B, Michaux L, et al. Identification of cytogenetic subclasses and recurring chromosomal aberrations in AML and MDS with complex karyotypes using M-FISH. Genes Chromosomes Cancer. 2002;33:60-72.
Nowell P, Finan J, Dalla Favera R, et al. Association of amplified oncogene c-myc with an abnormally banded chromosome 8 in a human leukaemia cell line. Nature. 1983;306:494-497.
Fugazza G, Bruzzone R, Puppo L, Patrone F, Sessarego M. Amplified c-MYC sequences localized by fluorescence in-situ hybridization on double minute chromosomes in acute myeloid leukemias. Leuk Res. 1997;21:703-709.
Mrózek K, Heinonen K, Theil KS, Bloomfield CD. Spectral karyotyping in patients with acute myeloid leukemia and a complex karyotype shows hidden aberrations, including recurrent overrepresentation of 21q, 11q, and 22q. Genes Chromosomes Cancer. 2002;34:137-153.
Schoch C, Hafenach T, Bursch S, et al. Loss of genetic material is more common than gain in acute myeloid leukemia with complex aberrant karyotype: a detailed analysis of 125 cases using conventional chromosome analysis and fluorescence in situ hybridization including 24-color FISH. Genes Chromosomes Cancer. 2002;35:20-29.
Avet-Loiseau H, Godon C, Li JY, et al. Amplification of the 11q23 region in acute myeloid leukemia. Genes Chromosomes Cancer. 1999;26:166-170.
Cuthbert G, Thompson K, McCullough S, et al. MLL amplification in acute leukaemia: a United Kingdom Cancer Cytogenetics Group (UKCCG) study. Leukemia. 2000;14:1885-1891.
Streubel B, Valent P, Jager U, et al. Amplification of the MLL gene on double minutes, a homogeneously staining region, and ring chromosomes in five patients with acute myeloid leukemia or myelodysplastic syndrome. Genes Chromosomes Cancer. 2000;27:380-386.
Crossen PE, Morrison MJ, Rodley P, Cochrane J, Morris CM. Identification of amplified genes in a patient with acute myeloid leukemia and double minute chromosomes. Cancer Genet Cytogenet. 1999;113:126-133.
Sait SNJ, Qadir MU, Conroy JM, Matsui S-I, Nowak NJ, Baer MR. Double minute chromosomes in acute myeloid leukemia and myelodysplastic syndrome: identification of new amplification regions by fluorescence in situ hybridization and spectral karyotyping. Genes Chromosomes Cancer. 2002;34:42-47.
Armstrong SA, Staunton JE, Silverman LB, et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet. 2002;30:41-47.
Ferrando AA, Armstrong SA, Neuberg DS, et al. Gene expression signatures in MLL-rearranged T-lineage and B-precursor acute leukemias: dominance of HOX dysregulation. Blood. 2003;102:262-268.
Rozovskaia T, Ravid-Amir O, Tillib S, et al. Expression profiles of acute lymphoblastic and myeloblastic leukemias with ALL-1 rearrangements. Proc Natl Acad Sci U S A. 2003;100:7853-7858.
Yeoh EJ, Ross ME, Shurtleff SA, et al. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell. 2002;1:133-143.
Mitelman F, ed. ISCN 1995. An International System for Human Cytogenetic Nomenclature. Basel, Switzerland: Karger; 1995.
Vandesompele J, De Paepe A, Speleman F. Elimination of primer-dimer artifacts and genomic coamplification using a two-step SYBR green I real-time RT-PCR. Anal Biochem. 2002;303:95-98.
Vandesompele J, De Preter K, Pattyn F, et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002;3: research 34.1-34.11.
Pattyn F, Speleman F, De Paepe A, Vandesompele J. RTPrimerDB: the real-time PCR primer and probe database. Nucleic Acids Res. 2003;31:122-123.
Allen RJ, Smith SD, Moldwin RL, et al. Establishment and characterization of a megakaryoblast cell line with amplification of MLL. Leukemia. 1998;12:1119-1127.
Yu BD, Hess JL, Horning SE, Brown GAJ, Korsmeyer SJ. Altered Hox expression and segmental identity in Mll-mutant mice. Nature. 1995;378:505-508.
Armstrong SA, Kung AL, Mabon ME, et al. Inhibition of FLT3 in MLL: validation of a therapeutic target identified by gene expression based classification. Cancer Cell. 2003;3:173-183.
Akao Y, Seto M, Yamamoto K, et al. The RCK gene associated with t(11;14) translocation is distinct from the MLL/ALL-1 gene with t(4;11) and t(11;19) translocations. Cancer Res. 1992;52:6083-6087.
Nakagawa Y, Morikawa H, Hirata I, et al. Overexpression of rck/p54, a DEAD box protein, in human colorectal tumours. Br J Cancer. 1999;80:914-917.
Squire JA, Thorner PS, Weitzman S, et al. Coamplification of MYCN and a DEAD box gene (DDX1) in primary neuroblastoma. Oncogene. 1995;10:1417-1422.
Arai Y, Hosoda F, Kobayashi H, et al. The inv(11)(p15q22) chromosome translocation of de novo and therapy-related myeloid malignancies results in fusion of the nucleoporin gene, NUP98, with the putative RNA helicase gene, DDX10. Blood. 1997;89:3936-3944.
Corvi R, Savelyeva L, Schwab M. Duplication of N-MYC at its resident site 2p24 may be a mechanism of activation alternative to amplification in human neuroblastoma cells. Cancer Res. 1995;55:3471-3474.
