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11q23 rearrangements (KMT2A) in therapy related leukaemias

Written1998-08Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

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Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho 9807/3 Mixed phenotype acute leukaemia with t(v;11q23); MLL rearranged
ICD-Morpho 9813/3 B lymphoblastic leukaemia/lymphoma with t(v;11q23); MLL rearranged
ICD-Morpho 9920/3 Therapy-related myeloid neoplasms
Atlas_Id 1131
Note 11q23 rearrangements are also -and more often- found in de novo leukaemia

Clinics and Pathology

Phenotype / cell stem origin these treatment related myelodysplasia (t-MDS) or leukaemias (t-AL) exhibit variable phenotypes: CMML or RAEB±T in MDS cases, AML most often (M4 or M5a mainly, M1, M2, M5b at times, ALL (and biphenotypic leukaemias), often CD19+; t(4;11) cases are frequently ALL cases.
Etiology 11q23 rearrangements in treatment related leukaemias were thought to be found mainly following a treatment with anti-topoisomerase II (epipodophyllotoxins) or with an intercalating topoisomerase II inhibitor (anthracyclins), as for some 21q22 rearrangements; actually, they may also be found after alkylating agents treatment and/or radiotherapy; the prior cancer is variable: breast cancer, non-Hodgkin lymphoma, Hodgkin disease, leukaemia, lung carcinoma, and other malignancies.
Epidemiology up to 30% of t(11;19)(q23;p13.1), 10% or more of t(9;11), 5% of t(4;11) and 5% of t(10;11) are found in secondary leukaemias: altogether 5 to 10% of 11q23 leukaemias are treatment related; these 11q23 second leukaemias are found at any age, from infancy to elder age.
Clinics latency for the outcome of the second leukaemia after the first cancer is often short (med 2 yrs), but highly variable, and may not depend on the type of treatment received; it is however most often shorter than in cases of second leukaemias associated with -5/del(5q) or with -7/del(7q).
Prognosis is poor, as in other therapy related leukaemias; in a recent excellent studyc (n=40), only 80% of patients achieved remission, 3/4 relapsed within a year; median remission duration being 5 mths.

Cytogenetics

Cytogenetics Morphological various 11q23 rearrangements may be found: - t(1;11)(p32;q23) - t(1;11)(q21;q23) - t(4;11)(q21;q23) - t(6;11)(q27;q23) - t(9;11)(p22;q23) - t(10;11)(p12;q23) - t(11;16)(q23;p13) - t(11;17)(q23;q25) - t(11;19)(q23;p13.3) - t(11;19)(q23;p13.1)
Additional anomalies del(6q), -7/del(7q), del(17p)

Genes involved and Proteins

Gene NameKMT2A (myeloid/lymphoid or mixed lineage leukemia)
Location 11q23.3
Dna / Rna 21 exons, spanning over 100 kb; 13-15 kb mRNA
Protein 431 kDa; contains two DNA binding motifs (a AT hook, and Zinc fingers), a DNA methyl transferase motif, a bromodomain; transcriptional regulatory factor; nuclear localisation.
Gene NameEPS15 (epidermal growth factor receptor pathway substrate 15)
Location 1p32.3
Note Variable gene, from a variable chromosome partner. This gene and the following one appear to have, in most cases, no apparent homology to each other; for DNA and protein description of each, refer to their gene entry.
Gene NameMLLT11 (ALL1 fused gene from chromosome 1q)
Location 1q21.3
Gene NameAFF1 (AF4/FMR2 family, member 1)
Location 4q21.3
Gene NameAFDN (afadin, adherens junction formation factor )
Location 6q27
Gene NameMLLT3 (myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila); translocated to, 3)
Location 9p21.3
Gene NameMLLT10 (myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila); translocated to, 10)
Location 10p12.31
Gene NameCREBBP (CREB binding protein)
Location 16p13.3
Gene NameMLLT1 (myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila); translocated to, 1)
Location 19p13.3
Gene NameELL (eleven nineteen lysin rich leukemia gene)
Location 19p13.11

Result of the chromosomal anomaly

Hybrid gene
Description 5' MLL - 3' partner
  
Fusion Protein
Description N-term AT hook and DNA methyltransferase from MLL fused to (little or most of) the partner C-term part.
  

Bibliography

Different genetic pathways in leukemogenesis for patients presenting with therapy-related myelodysplasia and therapy-related acute myeloid leukemia.
Pedersen-Bjergaard J, Pedersen M, Roulston D, Philip P
Blood. 1995 ; 86 (9) : 3542-3552.
PMID 7579462
 
Secondary acute leukemia and myelodysplastic syndrome with 11q23 abnormalities. EU Concerted Action 11q23 Workshop.
Secker-Walker LM, Moorman AV, Bain BJ, Mehta AB
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1998 ; 12 (5) : 840-844.
PMID 9593290
 

Citation

This paper should be referenced as such :
Huret, JL
11q23 rearrangements in therapy related leukaemias
Atlas Genet Cytogenet Oncol Haematol. 1998;2(4):140-141.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Anomalies/11q23secondLeukID1131.html


Other genes implicated (Data extracted from papers in the Atlas) [ 1 ]

Genes KMT2A

External links

arrayMapTopo ( C42) Morph ( 9807/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapTopo ( C42) Morph ( 9813/3) - 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]
 
 
Disease database11q23 rearrangements (KMT2A) in therapy related leukaemias
REVIEW articlesautomatic search in PubMed
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