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  • Review Article
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Disruption of differentiation in human cancer: AML shows the way

Key Points

  • Loss of differentiation is an important component in the pathogenesis of many cancers.

  • Acute myeloid leukaemia (AML) represents a salient example of a cancer that is characterized by a differentiation block.

  • Specific haematopoietic transcription factors are crucial for differentiation to particular lineages during normal differentiation, and are controlled by specific patterns of expression and protein interactions.

  • These same transcription factors are frequently disrupted in AML.

  • Some mechanisms of disruption involve the effect of fusion proteins that are generated by chromosomal translocations on haematopoietic transcription factors.

  • In other cases, in the absence of common translocations, the transcription factors themselves are mutated.

  • Characterizing these transcription-factor abnormalities has already affected classification schemes based on patient outcome.

  • These transcription-factor pathways represent important targets for therapeutic intervention.

Abstract

Although much is understood about the ways in which transcription factors regulate various differentiation systems, and one of the hallmarks of many human cancers is a lack of cellular differentiation, relatively few reports have linked these two processes. Recent studies of acute myeloid leukaemia (AML), however, have indicated how disruption of transcription-factor function can disrupt normal cellular differentiation and lead to cancer. This model involves lineage-specific transcription factors, which are involved in normal haematopoietic differentiation. These factors are often targeted in AML — either by direct mutation or by interference from translocation proteins. Uncovering these underlying pathways will improve the diagnosis and treatment of AML, and provide a working model for other types of human cancer, including solid tumours.

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Figure 1: Role of transcription factors in haematopoietic development.
Figure 2: PU.1 and GATA reciprocal antagonism during haematopoietic stem-cell lineage differentiation.
Figure 3: PU.1 and C/EBPα interacting proteins.
Figure 4: The t(8;21) AML1–ETO fusion protein can disrupt normal C/EBPα function by two mechanisms.

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Acknowledgements

I wish to acknowledge the many colleagues who have contributed to these ideas, both by supporting them and by constructive disagreements, with particular thanks to G. Gilliland for telling me on a weekly basis why I am wrong. I also thank K. Akashi and C. Stocking for providing unpublished material. I apologize in advance to those investigators whose work or contributions were not cited due to space limitations or oversight on my part. This work was supported by National Institutes of Health grants.

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DATABASES

Cancer.gov

acute lymphocytic leukaemia

acute myeloid leukaemia

chronic myelogenous leukaemia

LocusLink

Aml1

AML1

C/EBPα

C/EBPε

Cbfβ

CBFβ

ETO

FLT3

FOG

GATA1

G–CSF

GM–CSF

IL-6

JUN

M–CSF

Pu.1

PU.1

SCL

FURTHER INFORMATION

CancerCare information on AML

MedLine information on AML

Glossary

ACUTE MYELOID LEUKAEMIA

(AML). The most common acute leukaemia in adults. the leukaemic cells, or 'blasts', represent progenitors that are arrested in differentiation at a very early stage in myelopoiesis.

FLUORESCENCE IN SITU HYBRIDIZATION

(FISH). A powerful technique that is used to detect chromosome translocations and other chromosome alterations in leukaemia.

ACUTE LYMPHOCYTIC LEUKAEMIA

(ALL). Involves early lymphoid progenitors, and, along with acute myeloid leukaemia, comprises the acute leukaemias. This cancer is more common in children than adults.

MYELOID

In the haematopoietic system, myeloid refers to granulocytes and monocytes/macrophages and their precursors.

FLUORESCENCE-ACTIVATED CELL SORTING

(FACS). A method that is used to separate and classify blood cells and to assess the expression of surface molecules on single cells.

LEUCINE ZIPPER

A protein–protein interaction domain that was first described in C/EBPα, but was used by a number of transcription-factor families to mediate protein–protein interactions.

FRENCH–AMERICAN–BRITISH

(FAB). Refers to a classification system of acute myeloid leukaemia that is based on assessment of the stage of differentiation of blasts.

BIALLELIC MUTATIONS

Mutations of both alleles of a gene, often resulting in no normal function.

SINGLE-STRAND CONFORMATION POLYMORPHISM

(SSCP). A technique that is used to screen for mutations. It involves polymerase chain reaction, followed by resolution of amplified DNA by gel or capillary electrophoresis. This is quicker, but not as definitive as direct sequencing of genes of interest.

AML1–ETO

The fusion protein that is generated by the t(8;21) translocation found in FAB M2 acute myeloid leukaemia.

THERAPY-RELATED AML

In contrast to de novo AML, this leukaemia arises following (and presumably due to) chemotherapy and/or radiation therapy for a previous cancer.

DIFFERENTIATION THERAPY

In contrast to cytotoxic therapy, differentiation therapy is directed towards inducing normal differentiation of cancer rather than killing cancer cells.

ACUTE PROMYELOCYTIC LEUKAEMIA

(APL). A subtype of acute myeloid leukaemia that is characterized by translocations involving the retinoic-acid receptor-α (RARα), usually t(15;17), resulting in production of the PML–RARα oncoprotein.

PML–RARα

The fusion protein that is formed by an in-frame fusion of the PML gene on chromosome 15 and the retinoic-acid receptor-α on chromosome 17. Associated with t(15;17) acute promyelocytic leukaemia.

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Tenen, D. Disruption of differentiation in human cancer: AML shows the way. Nat Rev Cancer 3, 89–101 (2003). https://doi.org/10.1038/nrc989

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