Role of the transcription factor AML-1 in acute leukemia and hematopoietic differentiation

doi:10.1016/S0378-1119(00)00014-7

Gene

Volume 245, Issue 2, 21 March 2000, Pages 223-235

https://doi.org/10.1016/S0378-1119(00)00014-7 Get rights and content

Abstract

Chromosomal translocations affecting the AML-1 gene are among the most frequent aberrations found in acute leukemia. Because the AML-1 transcription factor is a critical regulator of hematopoeitic cell development, normal homeostasis is disrupted in cells containing these translocations. In this review we describe the mechanisms of transcriptional activation and repression by AML-1 and how this transcriptional control is disrupted by the chromosomal translocations that affect AML-1. Finally, we discuss how the mechanism of transcriptional repression by these chromosomal translocation fusion proteins is a possible target of therapeutic intervention in acute leukemia.

Introduction

Leukemia occurs when the homeostasis of normal hematopoiesis is disrupted, and the result is an abnormal accumulation of hematopoietic cells. This disruption of homeostasis occurs when differentiation along a hematopoietic lineage is blocked or when cells accumulate due to a failure to undergo programmed cell death. In contrast to solid tumors, a high percentage of leukemias are associated with nonrandom chromosomal translocations which disrupt genes residing in the breakpoint region of the translocation. The result can be either increased or aberrant transcription of a gene, creation of a fusion gene, or a combination of these two. The genes residing at these breakpoint regions are often master regulators of hematopoietic cell differentiation, apoptosis, or proliferation.

Acute myeloid leukemia-1 (AML-1) was first cloned as the target of chromosomal translocations in the t(8;21), which is found primarily in stage M2 acute myeloid leukemia (Erickson et al., 1992, Miyoshi et al., 1991, Nisson et al., 1992). The t(8;21) is found in approximately 12% of acute myeloid leukemias. This translocation fuses the N-terminus of AML-1 to nearly all of eight twenty one (ETO, also known as myeloid transforming gene 8, or MTG8) (Fig. 1) (Miyoshi et al., 1993). Subsequently, AML-1 was found to be disrupted by multiple translocations, four of which have been cloned (Fig. 1). The t(16;21) fuses AML-1 to an ETO-related gene termed MTG16 (Gamou et al., 1998). The t(3;21) is found in blast crises of chronic myelogenous leukemia and in therapy-related acute myeloid leukemia. This translocation fuses the first five or six exons of AML-1 to the EVI1 transcription factor (Mitani et al., 1994, Nucifora and Rowley, 1994, Nucifora et al., 1993). The t(12;21) is the most frequent translocation in B-cell leukemia, occurring in up to 30% of B-cell acute lymphoblastic leukemia (Golub et al., 1995, Romana et al., 1995, Shurtleff et al., 1995). The result is a fusion of the N-terminus of translocation-ets-leukemia (TEL) with nearly all of AML-1 (Golub et al., 1995, Romana et al., 1995, Shurtleff et al., 1995). Finally, the function of AML-1 is disrupted indirectly by the inv(16) that is found in 12–15% of acute myeloid leukemias (Liu et al., 1993). The inv(16) fuses MYH11, a smooth muscle myosin heavy chain gene, to core-binding-factor-β (CBFβ) (Ogawa et al., 1993, Wang et al., 1993), an AML-1 heterodimeric partner (Liu et al., 1993). Thus, translocations targeting the AML-1/CBFβ transcription factor complex are among the most frequent mutations in human leukemia.

Section snippets

The AML-1 transcription factor

The AML-1 gene expresses a range of transcripts (Levanon et al., 1996), which would be predicted to give rise to various proteins. However, AML-1B or AML-1b (AML-1b is identical to AML-1B except for a deletion of the N-terminal 27 amino acids) are the major protein isoforms consistently detected in cells (Fig. 1). The AML-1A protein (Fig. 1) lacks the transactivation domain and has been used in many experimental systems as a competitive inhibitor of the full-length protein, AML-1B (to be

Transcriptional activation

A number of promoters of hematopoietic specific genes are activated by AML-1, including the promoters for interleukin-3 (IL-3) (Uchida et al., 1997), granulocyte–macrophage colony-stimulating factor (GM-CSF) (Hohaus et al., 1995, Takahashi et al., 1995), the receptor for CSF-1 (CSF-1R) (Zhang et al., 1994), neutrophil elastase (Nuchprayoon et al., 1994), granzyme B, (Wargnier et al., 1995), myeloperoxidase (Suzow and Friedman, 1993), the defensin protein, NP3 (Westendorf et al., 1998), and

Transcriptional repression

The role of AML-1 as a transcriptional repressor is now well documented. The WRPY motif at the extreme C-terminus of AML-1 is similar to the WRPW motif found in the Drosophila hairy protein. In hairy, this motif is required for interaction with the Groucho corepressors (Fisher et al., 1996). AML-1 interacted with a mammalian homolog of Groucho, termed transducin-like enhancer of split-1 (TLE1) (Stifani et al., 1992), and this interaction contributed to repression by GAL4–AML-1 chimeric proteins

A role for AML-1 in viral enhancer function

CBFA1, the mouse homolog of AML-3 (Table 1), was identified as a DNA-binding factor for murine leukemia virus enhancers (Wang and Speck, 1992). A mutation of the AML-1 DNA binding site in the Moloney murine leukemia virus LTR site increased the latency time of disease (Speck et al., 1990). Interestingly, this mutation also led to a high incidence of erythroleukemia, a disease that is rarely seen with the parent Moloney virus (Speck et al., 1990).

Murine AML-1 was identified as PEBP2αA, an

The Runt and Lozenge proteins

As mentioned above, homologs of the AML-1/CBFβ complex are found in Drosophila melanogaster. Runt was the first AML-1 family member to be cloned (Kania et al., 1990). In addition, Brother and Big Brother are Drosophila homologs of CBFβ (Golling et al., 1996). Runt was identified genetically as required for segmentation, sex determination, and for neurogenesis (Duffy and Gergen, 1991, Duffy et al., 1991, Gergen and Wieschaus, 1986). During segmentation, Runt acts as a transcriptional repressor,

AML-2 and AML-3

Although AML-2 (CBFA3 or PEBP2αC, see Table 1) and AML-3 [CBFA1 or PEBP2αA, see Table 1)] are not currently implicated in human leukemia, AML-3 has a major role in bone development and will be briefly discussed here. The AML-2 and AML-3 genes have over 90% identity with AML-1 in the Runt domain and 50–60% identity in their C-terminal sequences. AML-2 is expressed in hematopoietic cells (Meyers et al., 1996), but has yet to be described as a target for chromosomal translocations. Although AML-3

Chromosomal translocations that disrupt AML-1

Although translocations that disrupt AML-1 function are found in a diversity of leukemias, it appears that they have a common function. Early work indicated that AML-1/ETO dominantly interfered with AML-1-mediated transactivation (Frank et al., 1995, Lenny et al., 1995, Meyers et al., 1995). The fusion protein repressed transcription at substoichiometric levels, indicating that it functions as an active repressor (Lutterbach et al., 1998a, Meyers et al., 1995). Deletion analysis indicated that

AML-1 and AML-1/ETO in myeloid differentiation

Leukemias are often associated with defects in differentiation. The function of AML-1/ETO in cell differentiation was first analyzed in the Kasumi-1 and SKNO-1 cells that were isolated from AML patients and which carry the t(8;21) (Sakakura et al., 1994). Antisense oligonucleotides (directed to the Runt domain) selectively inhibited growth of the t(8;21) carrying Kasumi-1 cells (Sakakura et al., 1994). The antisense oligonucleotides also induced a partially differentiated phenotype, as seen by

Conclusions

The frequent disruption of AML-1 by chromosomal translocations indicates a crucial role in myeloid and lymphoid differentiation. The lack of hematopoiesis in AML-1-deficient embryos supports the role of AML-1 as a critical factor for the development of the hematopoietic system. The translocations into the AML-1 locus create fusion proteins that interfere with AML-1-dependent transactivation. For AML-1/ETO and TEL/AML-1, corepressor proteins and histone deacetylase activity are important for

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ReviewRole of the transcription factor AML-1 in acute leukemia and hematopoietic differentiation

Abstract

Introduction

Section snippets

The AML-1 transcription factor

Transcriptional activation

Transcriptional repression

A role for AML-1 in viral enhancer function

The Runt and Lozenge proteins

AML-2 and AML-3

Chromosomal translocations that disrupt AML-1

AML-1 and AML-1/ETO in myeloid differentiation

Conclusions

Cell

Cell

Cell

Nature

Curr. Opin. Cell. Biol.

Blood

Blood

Blood

Cell

Cell

Cell

Biochem. Biophys. Res. Commun.

Cell

J. Biol. Chem.

Blood

Genomics

Cell

J. Biol. Chem.

Cell

Cell

Cancer Genet. Cytogenet.

Blood

Virology

Cell

Blood

Blood

Cell

Blood

The leukemic protein core binding factor beta (CBFβ)-smooth-muscle myosin heavy chain sequesters CBFA2 into cytoskeletal filaments and aggregates

Mol. Cell. Biol.

Negative regulation of granulocytic differentiation in the myeloid precursor cell line 32Dcl3 by ear-2, a mammalian homolog of Drosophila seven-up and a chimeric leukemogenic gene, AML1/ETO

Proc. Natl. Acad. Sci. USA

Groucho-dependent and -independent repression activities of Runt domain proteins

Mol. Cell. Biol.

Runt homology domain proteins in osteoblast differentiation: AML3/CBFA1 is a major component of a bone-specific complex

J. Cell. Biochem.

The t(8;21) translocation is not consistently associated with high Bcl-2 expression in de novo acute myeloid leukemias of adults

Clin. Cancer Res.

ALY, a context-dependent coactivator of LEF-1 and AML-1, is required for TCRα enhancer function

Genes Dev.

Functional analysis of the individual enhancer core sequences of polyomavirus: cell-specific uncoupling of DNA replication from transcription

Mol. Cell. Biol.

The fusion gene CBFβ-MYH11 blocks myeloid differentiation and predisposes mice to myelomonocytic leukemia

Nat. Genet.

Modulation of TEL transcription activity by interaction with the ubiquitin-conjugating enzyme UBC9

Proc. Natl. Acad. Sci. USA

A transcriptional co-repressor that interacts with nuclear hormone receptors

Nature

The capacity of polyomavirus enhancer binding protein 2αB (AML1/Cbfα2) to stimulate polyomavirus DNA replication is related to its affinity for the nuclear matrix

Mol. Cell. Biol.

Fusion between a novel Kruppel-like zinc finger gene and the retinoic acid receptor-alpha locus due to a variant t(11;17) translocation associated with acute promyelocytic leukaemia

Embo J.

Patterning of cells in the Drosophila eye by Lozenge, which shares homologous domains with AML1

Genes Dev.

The Drosophila segmentation gene runt acts as a position-specific numerator element necessary for the uniform expression of the sex-determining gene sex-lethal

Genes Dev.

Expression and function of the Drosophila gene runt in early stages of neural development

Development

ETS-core binding factor: a common composite motif in antigen receptor gene enhancers

Mol. Cell. Biol.

Identification of homeotic target genes in Drosophila melanogaster including nervy, a proto-oncogene homologue

Genetics

Both TEL and AML-1 contribute repression domains to the t(12;21) fusion protein

Mol. Cell. Biol.

The WRPW motif of the hairy-related basic helix–loop–helix repressor proteins acts as a 4-amino-acid transcription repression and protein–protein interaction domain

Mol. Cell. Biol.

The AML1/ETO fusion protein blocks transactivation of the GM-CSF promoter by AML1B

Review
Role of the transcription factor AML-1 in acute leukemia and hematopoietic differentiation