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t(9;11)(p21;q23) KMT2A/MLLT3

Written1997-12Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Updated2016-03Jeroen Knijnenburg, H. Berna Beverloo
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands. b.beverloo@erasmusmc.nl

Abstract Review on t(9;11)(p21;q23), with data on clinics, and the genes involved.

Keywords chromosome 9; chromosome 11; acute myeloid leukemia; KMT2A; MLLT3.

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho 9897/3 AML with t(9;11)(p22;q23); MLLT3-MLL
ICD-Morpho 9920/3 Therapy-related myeloid neoplasms
Atlas_Id 1001
 
  t(9;11)(p21;q23) G- banding (left) - Courtesy Jean-Luc Lai and Alain Vanderhaegen (top 2), Courtesy Diane H Norback, Eric B Johnson, and Sara Morrison-Delap, UW Cytogenetic Services (middle 2 and bottom 2); R-banding (right): top: - Courtesy Pascale Cornillet-Lefebvre and Stéphanie Struski, center top: t(9;11)+der(9)t(9;11) - Courtesy Christiane Chharrin; bottom 2: - Courtesy Hossein Mossafa. FISH (left) - Courtesy Pascale Cornillet-Lefebvre and Stéphanie Struski. The probe is MLL; one signal is on the normal 11, one signal on the der(11), and one signal (arrow) on the der(9); FISH (right) - Courtesy Hossein Mossafa (AN: abnormal).

Clinics and Pathology

Disease Acute myeloid leukemia (AML).
Phenotype / cell stem origin Most often found in acute monocytic and myelomonocytic leukaemias, although occasionally also seen in AML with or without maturation (WHO 2008).
M5 most often (especially M5a, M4); both found in de novo and therapy related AML with antitopoisomerase II drugs (epipodophyllotoxins, anthracyclins, actinomycin D).
Immunophenotype typically shows positivity for CD11, CD13, CD15 and CD33, but less often shows positivity for CD14, CD34 and lymphoid markers.
Epidemiology May occur at any age, but is more common in children, being present in 5-12% of paediatric and 1-2% of adult AML, and equally common in males and females.
Clinics Organomegaly, frequent central nervous system (CNS) involvement, especially in de novo cases; no preceding myelodysplastic phase, unlike classic therapy related AML with chromosome 5 and/or 7 involvement, short interval from initial drug therapy (may even be of 1-2 yrs). Patients may present with disseminated intravascular coagulation and may have tissue infiltration.
Cytology Absence of trilineage dysplasia, unlike classic therapy related AML.
Prognosis Survival is described as poor to intermediate, being superior to AML with other KMT2A translocations.
Cytogenetics

Cytogenetics Morphological May easily be overlooked. Previously described as t(9;11)(p22;q23) based on band estimation, but nowadays it is known that MLLT3 is located in 9p21.3 based on molecular positioning.
Cytogenetics Molecular FISH or RT-PCR is indicated in cases with poor chromosome morphology or in cases where the translocation is expected in cases based on morphology, immunophenotype or clinical presentation.
Additional anomalies None in 70% of cases, +8 in 20%, less frequently: additional trisomies of chromosome 6, 19 or 21.
Variants Complex 3 way translocations t(9;11;Var) involving a (variable) third chromosome and insertions have been described, and showed that der(11) is the crucial on

Genes involved and Proteins

Gene NameMLLT3 (myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila); translocated to, 3)
Location 9p21.3
Protein Contains a nuclear targeting sequence; transcriptional activator; nuclear localisation.
Gene NameKMT2A (myeloid/lymphoid or mixed lineage leukemia)
Location 11q23.3
Protein Contains two DNA binding motifs (a AT hook, and Zinc fingers), a DNA methyl transferase motif, a bromodomain; transcriptional regulatory factor; nuclear localisation.

Result of the chromosomal anomaly

Hybrid gene
Description 5' KMT2A- 3' MLLT3; variable breakpoints.
  
Fusion Protein
Description N-term -- AT hook and DNA methyltransferase from KMT2A (1444 amino acids) fused to the 192 C-term amino acids from MLLT3 (as breakpoints are variable, this is only an exemple); 180 kDa.
Expression Localisation Nuclear localisation.
  

To be noted

You may also have a glance at 11q23 rearrangements, which gives an overview of related diseases.

Bibliography

Implication of prior treatment with drug combinations including inhibitors of topoisomerase II in therapy-related monocytic leukemia with a 9;11 translocation.
Albain KS, Le Beau MM, Ullirsch R, Schumacher H
Genes, chromosomes & cancer. 1990 ; 2 (1) : 53-58.
PMID 2177642
 
Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study.
Balgobind BV, Raimondi SC, Harbott J, Zimmermann M, Alonzo TA, Auvrignon A, Beverloo HB, Chang M, Creutzig U, Dworzak MN, Forestier E, Gibson B, Hasle H, Harrison CJ, Heerema NA, Kaspers GJ, Leszl A, Litvinko N, Nigro LL, Morimoto A, Perot C, Pieters R, Reinhardt D, Rubnitz JE, Smith FO, Stary J, Stasevich I, Strehl S, Taga T, Tomizawa D, Webb D, Zemanova Z, Zwaan CM, van den Heuvel-Eibrink MM.
Blood 2009 ; 114(12):2489-2496.
PMID 19528532
 
Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet
Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, Dombret H, Fenaux P, Grimwade D, Larson RA, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz MA, Sierra J, Tallman MS, Löwenberg B, Bloomfield CD; European LeukemiaNet.
Blood. 2010 Jan 21;115(3):453-74.
PMID 19880497
 
Identification of MLL and chimeric MLL gene products involved in 11q23 translocation and possible mechanisms of leukemogenesis by MLL truncation.
Joh T, Kagami Y, Yamamoto K, Segawa T, Takizawa J, Takahashi T, Ueda R, Seto M
Oncogene. 1996 ; 13 (9) : 1945-1953.
PMID 8934541
 
Translocation t(9;11)(p21;q23) in pediatric de novo and secondary acute myeloblastic leukemia.
Sandoval C, Head DR, Mirro J Jr, Behm FG, Ayers GD, Raimondi SC
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1992 ; 6 (6) : 513-519.
PMID 1602790
 
WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW.
4th Edition; Lyon, France: IARC Press; 2008.
 

Citation

This paper should be referenced as such :
Knijnenburg J, Beverloo HB
t(9;11)(p21;q23) KMT2A/MLLT3;
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Anomalies/t0911ID1001.html
History of this paper:
Huret, JL. t(9;22)(q34;q11) in CML. Atlas Genet Cytogenet Oncol Haematol. 1997;1(2):98-100.
http://documents.irevues.inist.fr/bitstream/handle/2042/32071/12-1997-t0911ID1001.pdf


Other genes implicated (Data extracted from papers in the Atlas) [ 2 ]

Genes MLLT3 KMT2A

Translocations implicated (Data extracted from papers in the Atlas)

 t(9;11)(p22;q23) KMT2A/MLLT3

External links

KMT2A (11q23.3) MLLT3 (9p21.3)

Mitelman databaset(9;11)(p22;q23) [Case List]    t(9;11)(p22;q23) [Association List] Mitelman database (CGAP - NCBI)
arrayMapTopo ( C42) Morph ( 9897/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapTopo ( C42) Morph ( 9920/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
 
TICdbKMT2A/MLLT3  KMT2A (11q23.3) MLLT3 (9p21.3)
 
Disease databaset(9;11)(p21;q23) KMT2A/MLLT3
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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