11q23 rearrangements (KMT2A) in leukaemia

2003-08-01   Jean-Loup Huret  

1.Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers France

Clinics and Pathology

Disease

de novo and therapy related leukaemias; acute myeloid leukaemia (AML) and acute lymphocytic leukaemia (ALL) grossly represent half cases each; myelodysplasia (MDS) in the remaining 5%; biphenotypic leukaemia at times (likely to be more frequent with more investigations); 11q23 rearrangements in treatment related leukaemias (5-10% of 11q23 cases) are found mainly following a treatment with anti-topoisomerase II, or an intercalating topoisomerase II inhibitor, but also after alkylating agents treatment and/or radiotherapy; the prior cancer is variable.

Phenotype stem cell origin

AML: M5a in half cases, M4 (20%), M1 or M5b (10% each), M2 (5%); ALL: B-cell mostly, L1 or L2, CD19+ in 60% of B-ALL cases, CD10+ 35%; T-ALL in rare cases (

Epidemiology

25% are infant (

Clinics

organomegaly; frequent CNS involvement (5%); high WBC (> 50 X 109/l in 40%).
Atlas Image
Molecular studies have identified a human homologue of the drosophila trithorax gene (designed HRX or MLL). MLL is a developmental regulator and is structurally altered in leukemia associated translocations that show an abnormality at band 11q23. The MLL gene on 11q23 is involved in a number of translocations with different partner chromosomes. The most common translocations observed in childhood AML are the t(9;11)(p21;q23) and the t(11;19)(q23;p13.1); other translocations of 11q23 involve at least 30 different partners chromosomes. Molecular studies have shown that MLL is rearranged more frequently than is revealed by conventional cytogenetic studies. A partial tandem duplication of MLL gene has also been reported in the majority of adult patients whose leukemic blast cells have a +11 and in some with normal karyotype. There is a strong association between AML M5/M4 and deletion and translocations involving 11q23. Sometimes cases of 11q23 M5B and M4, and occasionally M2 or M1 also show MLL rearrangement. Two clinical subgroups of patients have a high frequency of 11q23 aberration and M5 subtypes: one is AML in infants with MLL rearrangement in about 50% of cases; the other group is "secondary leukemia" (sAML) potentially after treatment with DNA topoisomerase II inhibitors. In general the translocations in these leukemia are the same as those occurring in "de novo" leukemia i.e. t(9;11), t(11;19) - Text and iconography Courtesy Georges Flandrin 2001.

Prognosis

very poor in general; variable according to the translocation, the phenotype, the age , and whether the leukaemia is de novo or treatment related.

Cytogenetics

Cytogenetics morphological

  • I- the most frequent are:
  • normal karyotype: a partial tandem duplication (in situ) of MLL is present in a percentage of AML with a normal karyotype; LARG, in 11q23, has been found fused to MLL
  • +11 : 1% of AML and MDS as well; M1, M2, and M4 AML; therapy related AML; MDS evolving towards AML; partial tandem duplication (in situ) of MLL; visible dup(11q) also occur.
  • t(4;11)(q21;q23) : represent 1/3 of cases; found mainly (95%) in B-ALL (CD19+ in 75%, CD10+ in 15%); treatment related ALL in 5%; unbalanced sex ratio < 4 yrs (1M/2F); children represent half cases (infants (

    • Additional anomalies

    +X and i(7q) in the t(4;11); +8, +19, +21 in the t(6;11); +8 and +19 in the t(9;11); inv(11) in the t(10;11); +X, +6 and +8 in the 19p13.3; +8 in the 19p13.1

    Genes Involved and Proteins

    Gene name
    KMT2A (myeloid/lymphoid or mixed lineage leukemia)
    Location
    11q23.3
    Dna rna description
    21 exons, spanning over 100 kb; 13-15 kb mRNA; coding sequence: 11.9 kb.
    Protein description
    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; wide expression; homology with trithorax (drosophila).
    Gene name
    variable gene, from a variable chromosome partner (see above)
    Dna rna description
    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

    Atlas Image
    MLL and partners - Editor, 06/2000, last update 09/2001. We implore researchers not to discover further MLL partners: there is no more room.

    Description

    5 MLL- 3 partner; highly variable breakpoints on the partnerN-term AT hook and DNA methyltransferase from MLL fused to (little or most of) the partner C-term part; the reciprocal ( partner-MLL) may or may not be expressed.

    Article Bibliography

    Pubmed IDLast YearTitleAuthors
    21776421990Implication of prior treatment with drug combinations including inhibitors of topoisomerase II in therapy-related monocytic leukemia with a 9;11 translocation.Albain KS et al
    94794911998Cloning and characterization of three human forkhead genes that comprise an FKHR-like gene subfamily.Anderson MJ et al
    75429101995Molecular basis of 11q23 rearrangements in hematopoietic malignant proliferations.Bernard OA et al
    109086482000The human GRAF gene is fused to MLL in a unique t(5;11)(q31;q23) and both alleles are disrupted in three cases of myelodysplastic syndrome/acute myeloid leukemia with a deletion 5q.Borkhardt A et al
    98859821999MLL is involved in a t(2;11)(p21;q23) in a patient with acute myeloblastic leukemia.Fleischman EW et al
    95932861998Ten novel 11q23 chromosomal partner sites. European 11q23 Workshop participants.Harrison CJ et al
    109806222000AF15q14, a novel partner gene fused to the MLL gene in an acute myeloid leukaemia with a t(11;15)(q23;q14).Hayette S et al
    84264681993Cytogenetic heterogeneity in t(11;19) acute leukemia: clinical, hematological and cytogenetic analyses of 48 patients--updated published cases and 16 new observations.Huret JL et al
    93896841997Adenoviral E1A-associated protein p300 is involved in acute myeloid leukemia with t(11;22)(q23;q13).Ida K et al
    26745631989Characteristics of trisomy 11 in childhood acute leukemia with review of the literature.Ingram L et al
    95932881998Derivative chromosomes of 11q23-translocations in hematologic malignancies. European 11q23 Workshop participants.Johansson B et al
    34961351987Acute leukemia with chromosome translocation (4;11): 7 new patients and analysis of 71 cases.Lampert F et al
    95932841998The t(10;11)(p12;q23) translocation in acute leukaemia: a cytogenetic and clinical study of 20 patients. European 11q23 Workshop participants.Lillington DM et al
    95932821998The t(6;11)(q27;q23) translocation in acute leukemia: a laboratory and clinical study of 30 cases. EU Concerted Action 11q23 Workshop participants.Martineau M et al
    96009801998t(11;22)(q23;q11.2) In acute myeloid leukemia of infant twins fuses MLL with hCDCrel, a cell division cycle gene in the genomic region of deletion in DiGeorge and velocardiofacial syndromes.Megonigal MD et al
    95932851998The translocations, t(11;19)(q23;p13.1) and t(11;19)(q23;p13.3): a cytogenetic and clinical profile of 53 patients. European 11q23 Workshop participants.Moorman AV et al
    81618081994Childhood acute lymphoblastic leukemia with the t(4;11)(q21;q23): an update.Pui CH et al
    19911611991Clinical characteristics and treatment outcome of childhood acute lymphoblastic leukemia with the t(4;11)(q21;q23): a collaborative study of 40 cases.Pui CH et al
    92261521997All patients with the T(11;16)(q23;p13.3) that involves MLL and CBP have treatment-related hematologic disorders.Rowley JD et al
    8558942199611q23 rearrangements in acute leukemia.Rubnitz JE et al
    78373911995Self-fusion of the ALL1 gene. A new genetic mechanism for acute leukemia.Schichman SA et al
    95932901998Secondary acute leukemia and myelodysplastic syndrome with 11q23 abnormalities. EU Concerted Action 11q23 Workshop.Secker-Walker LM et al
    95932831998Hematological malignancies with t(9;11)(p21-22;q23)--a laboratory and clinical study of 125 cases. European 11q23 Workshop participants.Swansbury GJ et al
    105887401999AF5q31, a newly identified AF4-related gene, is fused to MLL in infant acute lymphoblastic leukemia with ins(5;11)(q31;q13q23).Taki T et al
    96946991998ABI-1, a human homolog to mouse Abl-interactor 1, fuses the MLL gene in acute myeloid leukemia with t(10;11)(p11.2;q23).Taki T et al
    89770381996Chromosome abnormalities in leukaemia: the 11q23 paradigm.Young BD et al

    Citation

    Jean-Loup Huret

    11q23 rearrangements (KMT2A) in leukaemia

    Atlas Genet Cytogenet Oncol Haematol. 2003-08-01

    Online version: http://atlasgeneticsoncology.org/haematological/1030/11q23-rearrangements-(kmt2a)-in-leukaemia

    Historical Card

    2001-01-01 11q23 rearrangements (KMT2A) in leukaemia by  Jean-Loup Huret 

    Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers France

    1998-08-01 11q23 rearrangements (KMT2A) in leukaemia by  Jean-Loup Huret 

    Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers France