MLL amplification in leukemia

2010-05-01   Anwar Mohamed 

1.Cytogenetics Laboratory, Pathology Department, Wayne State University School of Medicine, Detroit Medical Center, Detroit, MI 48201, USA

Clinics and Pathology

Disease

De novo acute myeloid leukemia (AML), de novo myelodysplastic syndromes (MDS), therapy-related AML, therapy-related MDS, and AML transforming from MDS.

Phenotype stem cell 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

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.

Cytogenetics

Cytogenetics morphological

MLL amplification appears in variable cytogenetics manifestations including hsr, dmin, ring chromosome, derivative 11q, and marker chromosome.

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.

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.

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.
Gene name
KMT2A (myeloid/lymphoid or mixed lineage leukemia)
Location
11q23.3
Protein description
MLL is homologous to the transcriptional regulator 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.

Bibliography

Pubmed IDLast YearTitleAuthors
112840332001Duplication 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.Andersen MK et al
120345192002MLL amplification in myeloid malignancies: clinical, molecular, and cytogenetic findings.Dolan M et al
164250252006Del(5q) and MLL amplification in homogeneously staining region in acute myeloblastic leukemia: a recurrent cytogenetic association.Herry A et al
194809362009Association of MLL amplification with poor outcome in acute myeloid leukemia.Maitta RW et al
109183922000MLL amplification in myeloid leukemias: A study of 14 cases with multiple copies of 11q23.Michaux L et al
174522542007MLL amplification in acute myeloid leukemia.Pajuelo-Gámez JC et al
160267822005Oncogene amplification in transforming myelodysplasia.Papenhausen PR et al
129469922004Expression analyses identify MLL as a prominent target of 11q23 amplification and support an etiologic role for MLL gain of function in myeloid malignancies.Poppe B et al
196024632009Gene amplification in myeloid leukemias elucidated by fluorescence in situ hybridization.Rayeroux KC et al
107193682000Amplification of the MLL gene on double minutes, a homogeneously staining region, and ring chromosomes in five patients with acute myeloid leukemia or myelodysplastic syndrome.Streubel B et al
193063562009AML/MDS with 11q/MLL amplification show characteristic gene expression signature and interplay of DNA copy number changes.Zatkova A et al
149787882004Distinct sequences on 11q13.5 and 11q23-24 are frequently coamplified with MLL in complexly organized 11q amplicons in AML/MDS patients.Zatkova A et al

Summary

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.
Atlas Image
MLL amplification A: Metaphase, FISH, and G-banded karyotype: Markers with MLL amplification and r(11) (top and bottom left - Courtesy Thomas Boyer; FISH using the LSI MLL breakapart probe (Vysis, Inc) showing MLL gene amplification in acute myeloid leukemia (bottom right) - Courtesy Anwar Mohamed. B: R-banded karyotype and FISH using the LSI MLL breakapart probe (Vysis, Inc) showing MLL/KMT2A gene amplification in acute myeloid leukemia - Courtesy Karolien Beel, Peter Meeus and Lucienne Michaux. C: Fluorescence in situ hybridization with whole chromosome 11 probe (Metasystems, Germany) showing chromosome 11 sequences on multiple chromosomes (A,B) and hybridization with Vysis LSI MLL dual color, break apart probe (Abbott Molecular, US), showing multiple copies of the MLL (KMT2A) gene on 11q23.3 (red-green or a fused yellow signal), indicative of gene amplification. Courtesy Adriana Zamecnikova.

Citation

Anwar Mohamed

MLL amplification in leukemia

Atlas Genet Cytogenet Oncol Haematol. 2010-05-01

Online version: http://atlasgeneticsoncology.org/haematological/1547/mll-amplification-in-leukemia

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