11q23 rearrangements in therapy related leukaemias

Identity

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 RAEBħT in MDS cases, ANLL 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 Name	MLL
Location	11q23
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 Name	variable gene, from a variable chromosome partner: AF1p (1p32) AF1q (1q21) AF4 (4q21) AF6 (6q27) AF9 (9p22) AF10 (10p12) CBP (16p13) ENL (19p13.3) ELL (19p13.1)
Dna / Rna	these genes appear to have, in most cases, no apparent homology to each other; for DNA and protein description of each, refer to their gene entry.

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

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

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

Contributor(s)

Written	08-1998	Jean-Loup Huret

Citation

This paper should be referenced as such :

Huret JL . 11q23 rearrangements in therapy related leukaemias. Atlas Genet Cytogenet Oncol Haematol. August 1998 . URL : http://AtlasGeneticsOncology.org/Genes/11q23secondLeukID1131.html

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