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(Paper co-edited with the European LeukemiaNet)
Amplification of MLL gene in a new case of acute myeloid leukemia
Written2010-05Sayf Alkatib, Deborah Schloff, Anwar N Mohamed
Cytogenetics Laboratory, Pathology Department, Wayne State University School of Medicine, Detroit Medical Center, Detroit MI, USA
Age and sex : 75 year(s) old female patient.
Previous History : no preleukemia
no previous malignant disease
no inborn condition of note
Organomegaly : no hepatomegaly ; no splenomegaly ; no enlarged lymph nodes ; no central nervous system involvement
WBC : 3.00 x 109/L ; Hb : 9.0 g/dL ; platelets : 37.000 x 109/L; blasts : 18% % .
Bone marrow : 90 Hypercellular (90%) bone marrow with at least 30% blasts. There was dysplasia in all three cell lines.
Cyto pathology classification
Cytology : MDS/AML
Immunophenotype : Flow cytometry identified a population of blasts of myeloid origin encompassing 31% of cells. The blasts were expressing CD13, CD33, CD34, CD117, HLA-DR, and CD56.
Rearranged Ig Tcr : Not performed.
Pathology : Increased and poorly maturing myeloid leukogenesis. Increased erythrocytogenesis with dysplastic forms (nuclear budding and megaloblastoid changes). Megakaryocytogenesis was markedly increased with dysplastic forms (hypolobulated and multiple widely separated nuclei).
Electron microscopy : Not performed.
Precise diagnosis : Acute myeloid leukemia with multilineage dysplasia.
Date of diagnosis: 09-2009
Treatment : Gemtuzumab Ozogamicin, and 5-Azacitidine.
Complete remission : None
Status : Dead 11-2009
Survival : 2 month(s)
Sample : Bone marrow aspirate ; culture time : 24 h, without stimulating agents and 48hr with 10% conditioned medium ; banding : GTG.
Results : Analysis of 20 metaphase cells revealed an abnormal female karyotype in all metaphases. Very complex chromosomal abnormalities were identified. karyotype was designated; 45,X,add(X)(q22),-3,del(5)(q13q33),hsr(11)(q23),add(12)(p11.2),-17,+r[cp20].
Other molecular studies
technics : Fluorescence in situ hybridization (FISH) using the LSI EGR1/(5q31)/ D5S23:D5S721 dual color, LSI MLL/11q23 dual color breakapart DNA probes, and whole chromosome paint (WCP) 11 was performed (Vysis Inc. Downers Grove, IL).
results : Deletion of EGR1/5q31 was seen in 25% of cells and amplification of MLL/11q23 gene was found in 60% of cells. MLL signals appeared fused indicating lack of MLL rearrangement.
G-banded karyotype showing 45,X,add(X)(q22),-3,del(5)(q13q33), hsr(11)(q23),add(12)(p11.2),-17,+r[cp20].
FISH with LSI MLL/11q23 probe showing amplification of MLL gene (arrow) along with one normal copy.
WCP 11 spectrum green on the same metaphase in figure 2 showing two painting signals indicating that the amplified MLL located on chromosome 11 (arrow).
The case described here is of a 75-year-old female who was diagnosed with AML with multilineage dysplasia. Cytogenetics revealed a complex aberrant karyotype (CAK) including deletion of 5q and loss of chromosome 17. In addition, FISH confirmed deletion of EGR1/5q31 and showed amplification of MLL/11q23 gene in the form of hsr at 11q. Literature suggests an association of amplification of MLL with CAK. Moreover, deletions of 5/5q and 17/17p, such as in our case, are frequently found along with MLL amplification. Previously reported AML cases with MLL amplifications tend to occur in elderly patients, and are characterized by rapid progression, poor response to treatment, and poor clinical outcome. The present case supports the notion that MLL amplification is commonly found in the setting of CAK with deletion of chromosome 5 and 17. Thus, the presence of MLL amplification along with deletion 5q in AML cases appears to be a genomic pattern which signifies a poor prognosis in elderly patients.
Internal links
Atlas CardMLL amplification in leukemia
MLL amplification in myeloid leukemias: A study of 14 cases with multiple copies of 11q23.
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.
Genes Chromosomes Cancer. 2000 Sep;29(1):40-7.
PMID 10918392
MLL amplification in myeloid malignancies: clinical, molecular, and cytogenetic findings.
Dolan M, McGlennen RC, Hirsch B.
Cancer Genet Cytogenet. 2002 Apr 15;134(2):93-101.
PMID 12034519
Expression 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, 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.
Blood. 2004 Jan 1;103(1):229-35. Epub 2003 Aug 28.
PMID 12946992
Distinct sequences on 11q13.5 and 11q23-24 are frequently coamplified with MLL in complexly organized 11q amplicons in AML/MDS patients.
Zatkova A, Ullmann R, Rouillard JM, Lamb BJ, Kuick R, Hanash SM, Schnittger S, Schoch C, Fonatsch C, Wimmer K.
Genes Chromosomes Cancer. 2004 Apr;39(4):263-76.
PMID 14978788
Oncogene amplification in transforming myelodysplasia.
Papenhausen PR, Griffin S, Tepperberg J.
Exp Mol Pathol. 2005 Oct;79(2):168-75.
PMID 16026782
Del(5q) and MLL amplification in homogeneously staining region in acute myeloblastic leukemia: a recurrent cytogenetic association.
Herry A, Douet-Guilbert N, Gueganic N, Morel F, Le Bris MJ, Berthou C, De Braekeleer M.
Ann Hematol. 2006 Apr;85(4):244-9. Epub 2006 Jan 20.
PMID 16425025
MLL amplification in acute myeloid leukemia.
Pajuelo-Gamez JC, Cervera J, Garcia-Casado Z, Mena-Duran AV, Valencia A, Barragan E, Such E, Bolufer P, Sanz MA.
Cancer Genet Cytogenet. 2007 Apr 15;174(2):127-31.
PMID 17452254
Association of MLL amplification with poor outcome in acute myeloid leukemia.
Maitta RW, Cannizzaro LA, Ramesh KH.
Cancer Genet Cytogenet. 2009 Jul;192(1):40-3.
PMID 19480936
AML/MDS with 11q/MLL amplification show characteristic gene expression signature and interplay of DNA copy number changes.
Zatkova A, Merk S, Wendehack M, Bilban M, Muzik EM, Muradyan A, Haferlach C, Haferlach T, Wimmer K, Fonatsch C, Ullmann R.
Genes Chromosomes Cancer. 2009 Jun;48(6):510-20.
PMID 19306356


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