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MLL translocations, histone modifications and leukaemia stem-cell development

Key Points

  • Mixed lineage leukaemia (MLL) translocations define a unique group of leukaemias, which phenotypically can be defined as acute myeloid leukaemias (AML), acute lymphoblastic leukaemias (ALL) or biphenotypic (mixed lineage) leukaemias (MLL).

  • MLL is a methyltransferase that is involved in the positive regulation of Hox gene expression and methylation of histone H3 lysine residue 4 (H3K4).

  • As a result of inter-chromosomal translocations, the N terminus of MLL can be 'fused' to the C terminus of over 50 different partners, which results in the loss of the H3K4 methyl transferase domain.

  • A major group of MLL fusion partners appear to interact with the DOT1L methyltransferase that positively regulates transcription by methylation of histone H3 lysine residue 79 (H3K79).

  • MLL fusion proteins efficiently transform haematopoietic precursors to leukaemia stem cells.

Abstract

Translocations that involve the mixed lineage leukaemia (MLL) gene identify a unique group of acute leukaemias, and often predict a poor prognosis. The MLL gene encodes a DNA-binding protein that methylates histone H3 lysine 4 (H3K4), and positively regulates gene expression including multiple Hox genes. Leukaemogenic MLL translocations encode MLL fusion proteins that have lost H3K4 methyltransferase activity. A key feature of MLL fusion proteins is their ability to efficiently transform haematopoietic cells into leukaemia stem cells. The link between a chromatin modulator and leukaemia stem cells provides support for epigenetic landscapes as an important part of leukaemia and normal stem-cell development.

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Figure 1: Distribution of major MLL fusion partner genes in de novo childhood and adult leukaemias.
Figure 2: Schematic representation of the MLL protein and MLL fusions.
Figure 3: Histone methylation and transcription.
Figure 4: Gene-expression programmes of normal myeloid cells compared with MLL–AF9 leukaemia stem cells.
Figure 5: The leukaemia cell of origin and the LSC phenotype.

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Acknowledgements

We would like to thank members of the Armstrong laboratory for helpful comments and Elise Porter for administrative assistance. We recognize that there are a number of aspects of MLL-mediated biology that we were unable to cover in this Review, and direct readers to a number of recent reviews that cover other aspects of this interesting topic. We apologize to those that we have been unable to reference owing to space constraints.

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Correspondence to Scott A. Armstrong.

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Atlas of Genetics and Cytogenetics in Oncology and Haematology

Glossary

Biphenotypic leukaemia

An acute leukaemia where leukaemic blasts express both myeloid and lymphoid antigens such as CD14 and CD19, respectively. Normally, such cells are not found in haematopoietic organs.

Immunophenotype

A combination of cell surface antigens recognized by fluorescent-dye-labelled antibodies that are used to define a specific cell type.

Aorta–gonad–mesonephros region

A region in the mouse embryo that is believed to be the origin of definitive haematopoiesis and where the first definitive haematopoietic stem cell appears to develop.

Breakpoint cluster region

A region on a chromosome that is a frequent site of involvement in interchromosomal translocations.

Nuclear matrix

A protein matrix that provides a scaffold for nuclear organization and to which chromatin is attached.

Cyclophilin

An enzyme with peptidyl prolyl isomerase activity, which catalyses the isomerization of peptide bonds from trans to cis form at proline residues and facilitates protein folding.

Self renewal

The ability of a cell to replicate such that it produces at least one progeny cell that retains all of the developmental and proliferative potential of the mother cell. A self-renewing division can produce either two cells with all properties of the mother cell or one cell with all properties of the mother cell and one cell that is more differentiated.

Granulocyte macrophage progenitor

(GMP). A progenitor cell in bone marrow that can give rise to terminally differentiated monocytes, macrophages, and neutrophils, but not other haematopoietic cells such as megakaryocytes, red blood cells, B or T natural killer cells, or dendritic cells. GMPs are incapable of self renewal.

BCR-ABL

A leukaemogenic fusion protein that is a result of reciprocal translocation between chromosome 9 and chromosome 22. The 5′ section of BCR from chromosome 9 is fused to most of the proto-oncogene ABL from chromosome 22.

Rapamycin

An immunosuppressive drug that inhibits mammalian target of rapamycin (mTOR). Rapamycin and other mTOR inhibitors are being assessed as potential therapeutics in a number of cancers, including leukaemias.

PTEN

Mutations in the PTEN tumour suppressor are found in many common human tumour types, including glioma, endometrial adenocarcinoma, melanoma and prostate adenocarcinoma.

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Krivtsov, A., Armstrong, S. MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer 7, 823–833 (2007). https://doi.org/10.1038/nrc2253

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