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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Mini Review MLL amplification in leukemia Anwar Mohamed Cytogenetics Laboratory, Pathology Department, Wayne State University School of Medicine, Detroit Medical Center, Detroit, MI 48201, USA (AM) Published in Atlas Database: May 2010 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/MLLampliID1547.html DOI: 10.4267/2042/44971 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology myelodysplastic syndromes (MDS), therapy-related AML, therapy-related MDS, and AML transforming from MDS. Identity Note Recently, amplification of MLL/11q23 gene has been reported as another recurrent amplified gene in myeloid malignancy. It is mainly associated with elderly patients, often dysplastic bone marrow, and complex karyotypic abnormalities. It is suggested that MLL gain of function is the mechanism that contributes to the rapid progression and dismal outcome of this leukemia. Phenotype/cell stem origin Generally patients presented with anemia, low platelets, and often leukocytosis. AML are most often FAB subtypes M4 and M5 (particularly M5a), followed by M1, M2. MDS are mostly RAEB showing multilineage dysplasia. The leukemic cells are positive for CD45, CD13, CD15, CD33, CD34, HLA-DR. Epidemiology The exact incidence of MLL amplification in myeloid malignancies is difficult to establish. In large studies, MLL amplification has been found in < 1% of AML/MDS with abnormal karyotype. Amplification of MLL gene is the second most amplified gene in AML/MDS after CMYC oncogene. In one study, MLL amplification was found in 8/27 (29%) AML cases exhibiting homogenously staining region (hsr) and double minutes (dmin). AML/MDS with MLL amplification is associated with an elderly age, a median age at presentation of 72 years, ranged from 4 to 91 years, often prior history of therapy with alkylating agents or topoisomerase II, and slight female predominance. In therapy-related MDS/AML amplification of MLL gene was found in 12% patients. Prognosis FISH using the LSI MLL breakapart probe (Vysis, Inc) showing MLL gene amplification in acute myeloid leukemia. Generally, leukemia with MLL amplification is associated with an aggressive clinical course with poor response to chemotherapy, and extremely short survival. The median survival of the patients with available data is 2-3 months. Clinics and pathology Disease De novo acute myeloid leukemia (AML), de novo Atlas Genet Cytogenet Oncol Haematol. 2011; 15(2) 220 MLL amplification in leukemia Mohamed A Drosophila trithorax (trx) protein, which is involved in the regulation of HOX gene expression. MLL plays an essential role in embryonic development, also as regulator of growth of hematopoietic precursors. Cytogenetics Cytogenetics morphological MLL amplification appears in variable cytogenetics manifestations including hsr, dmin, ring chromosome, derivative 11q, and marker chromosome. To be noted Case Report Amplification of MLL gene in a new case of acute myeloid leukemia Cytogenetics molecular FISH has been useful in detecting MLL amplification. In many cases, the MLL amplification was suspected by conventional banded chromosomes, but was confirmed by FISH instead. Most cases are identified on the basis of multiple MLL signals by FISH. The number of copies of MLL is quit variable ranging from 5 to 90 copies per cell, and Southern blot analysis reveals a germline configuration of the amplified MLL gene in majority of cases. Simultaneous amplification of MLL and CMYC oncogenes on different chromosomal regions has been reported in at least two cases. References Michaux L, Wlodarska I, Stul M, Dierlamm J, Mugneret F, Herens C, Beverloo B, Verhest A, Verellen-Dumoulin C, Verhoef G, Selleslag D, Madoe V, Lecomte M, Deprijck B, Ferrant A, Delannoy A, Marichal S, Duhem C, Dicato M, Hagemeijer A. MLL amplification in myeloid leukemias: A study of 14 cases with multiple copies of 11q23. Genes Chromosomes Cancer. 2000 Sep;29(1):40-7 Streubel B, Valent P, Jäger U, Edelhäuser M, Wandt H, Wagner T, Büchner T, Lechner K, Fonatsch C. 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 Apr;27(4):380-6 Additional anomalies The majority of patients with MLL amplifications have complex aberrant karyotype, often hypodiploid; over 50% of them have five or more chromosomal abnormalities. No patient with normal karyotype was found. Recurrent chromosomal abnormalities seen in association with MLL/11q amplifications are -5/5q-, 7/7q-, -17/17p-, -18/18q-, and missing or structural abnormality of 11q. As determined by chromosome analysis, deletion of 5/5q and 17/17p are seen in approximately 80% and 50% respectively in AML/MDS cases exhibiting MLL amplification. Andersen MK, Christiansen DH, Kirchhoff M, PedersenBjergaard 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 May;31(1):33-41 Dolan M, McGlennen RC, Hirsch B. MLL amplification in myeloid malignancies: clinical, molecular, and cytogenetic findings. Cancer Genet Cytogenet. 2002 Apr 15;134(2):93-101 Poppe B, Vandesompele J, Schoch C, Lindvall C, Mrozek K, Bloomfield CD, Beverloo HB, Michaux L, Dastugue N, Herens C, Yigit N, De Paepe A, Hagemeijer A, Speleman F. Expression analyses identify MLL as a prominent target of 11q23 amplification and support an etiologic role for MLL gain of function in myeloid malignancies. Blood. 2004 Jan 1;103(1):229-35 Genes involved and proteins Note Generally MLL amplification is not associated with rearrangement of this gene. RNA overexpression is the result of the increase copy number of MLL (gain of function). Moreover, the amplified region is not limited to the MLL/11q23.3 gene locus, and other genes in the MLL flanking region have been also amplified. FISH and other molecular techniques have identified genes at 11q such as DDX6, GAB2, ETS1, FLI1, SNX19 and/or NFRKB being co-amplified. The size and number of amplicons are variable and at least 9 regions have been identified at 11q23-q25. In addition, over 90% of AML/MDS cases with MLL amplification show an inactivation of TP53 by deletion or mutation indicating that functional TP53 loss is an important key alteration in this leukemia. Zatkova A, Ullmann R, Rouillard JM, Lamb BJ, Kuick R, Hanash SM, Schnittger S, Schoch C, Fonatsch C, Wimmer K. Distinct sequences on 11q13.5 and 11q23-24 are frequently coamplified with MLL in complexly organized 11q amplicons in AML/MDS patients. Genes Chromosomes Cancer. 2004 Apr;39(4):263-76 Papenhausen PR, Griffin S, Tepperberg J. Oncogene amplification in transforming myelodysplasia. Exp Mol Pathol. 2005 Oct;79(2):168-75 Herry A, Douet-Guilbert N, Guéganic N, Morel F, Le Bris MJ, Berthou C, De Braekeleer M. Del(5q) and MLL amplification in homogeneously staining region in acute myeloblastic leukemia: a recurrent cytogenetic association. Ann Hematol. 2006 Apr;85(4):244-9 Pajuelo-Gámez JC, Cervera J, García-Casado Z, Mena-Durán AV, Valencia A, Barragán E, Such E, Bolufer P, Sanz MA. MLL amplification in acute myeloid leukemia. Cancer Genet Cytogenet. 2007 Apr 15;174(2):127-31 MLL (Mixed Lineage Leukemia) Location 11q23.3 Protein MLL is homologous to the transcriptional regulator Atlas Genet Cytogenet Oncol Haematol. 2011; 15(2) Maitta RW, Cannizzaro LA, Ramesh KH. Association of MLL amplification with poor outcome in acute myeloid leukemia. Cancer Genet Cytogenet. 2009 Jul;192(1):40-3 221 MLL amplification in leukemia Mohamed A Rayeroux KC, Campbell LJ. Gene amplification in myeloid leukemias elucidated by fluorescence in situ hybridization. Cancer Genet Cytogenet. 2009 Aug;193(1):44-53 copy number changes. Genes Chromosomes Cancer. 2009 Jun;48(6):510-20 This article should be referenced as such: Zatkova A, Merk S, Wendehack M, Bilban M, Muzik EM, Muradyan A, Haferlach C, Haferlach T, Wimmer K, Fonatsch C, Ullmann R. AML/MDS with 11q/MLL amplification show characteristic gene expression signature and interplay of DNA Atlas Genet Cytogenet Oncol Haematol. 2011; 15(2) Mohamed A. MLL amplification in leukemia. Atlas Genet Cytogenet Oncol Haematol. 2011; 15(2):220-222. 222