Download Leukaemia Section MLL amplification in leukemia Atlas of Genetics and Cytogenetics

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