The Aml1‐eto Chimaeric Transcription Factor in Acute Myeloid Leukaemia: Biology and Clinical Significance

Abstract

Acute myeloid leukaemia (AML) is a heterogenous disease, with individual cases showing variability in clinical presentation, blast cell morphology, therapeutic response and long-term prognosis. This heterogeneity extends to the molecular genetic lesions underlying the pathogenesis of AML. Although nonrandom clonal chromosomal aberrations are present in the majority of cases, each abnormality affects only a limited subset of cases. Nonetheless, recent studies have demonstrated that several chromosomal rearrangements, and the molecular abnormalities they produce, identify distinct patient subgroups with predictable clinical features and therapeutic responses.One of the most frequent cytogenetic abnormalities in AML is t(8;21)(q22;q22). The cloning of the genes targeted by this translocation led to the identi®cation of AML1 as the DNA-binding subunit of the AML1/CBFb core binding factor transcription complex, a critical regulator of normal haemopoiesis. Subsequent studies have demonstrated that the genes encoding this transcription factor complex are the most common targets of chromosomal rearrangements in human leukaemia. In this review I will summarize our understanding of the normal function of AML1/CBFb in haemopoiesis, and will then describe the mechanism through which t(8;21) induces leukaemia. Throughout I will emphasize the clinical signi®cance of this genetic lesion and the general principles of haemopoietic transformation that have emerged from study of the activity of the encoded chimaeric oncoprotein. Clinical features associated with t(8;21)-containing leukaemiaThe t(8;21) translocation is found in approximately 10±15% of AML cases and is frequently the only cytogenetic abnormality present in the leukaemic blasts (Hagemeijer et al, 1984;Bitter et al, 1987). Patients with this subtype of AML typically present with FAB AML-M2 morphology, in which the leukaemic blasts have prominent Auer rods, strong myeloperoxidase positivity, homogenous salmoncoloured granules, cytoplasmic vacuolization, and prominent bone marrow eosinophilia (Bitter et al, 1987). In addition, the leukaemic blasts frequently have a distinct immunophenotype, characterized by positivity for the B-cellassociated marker CD19, as well as CD13, CD34 and CD56 positivity (Hurwitz et al, 1992). This combination of ®ndings strongly suggests the presence of t(8;21). In fact, > 90% of t(8;21)-containing leukaemias have FAB AML-M2 morphology, and as many as 30±40% of FAB-M2 cases have this chromosomal translocation (Hagemeijer et al, 1984;Bitter et al, 1987). Interestingly, t(8;21)-containing leukaemias frequently form extramedullary tumours or chloromas (Swirsky et al, 1984). Despite this tendency for bulk disease, the presence of t(8;21) is associated with a high remission rate and prolonged disease-free survival in patients treated with standard induction and consolidation chemotherapy (Bloom®eld et al, 1998;Grimwade et al, 1998). Identi®cation of genes targeted by t(8;21)The 8;21 translocation was molecularly cloned in 1991 and shown to rearrang...

Correlation between karyotype and quantitative immunophenotype in acute myelogenous leukemia with t(8;21)

“…It has been shown that AML1-ETO protein can regulate the transcription of many genes important for hematopoiesis including the M-CSF receptor, the G-CSF receptor and BCL2 (all upregulated) as well as GM-CSF, TCR subunits (a, b and d), NP3 and MDR1 (all downregulated). 25 In addition, the AML1-ETO chimeric protein leads to dysplastic granulopoiesis in a knockin mice model. 26 Dysplastic granulopoiesis, a high density of G-CSF and M-CSF receptors and a low density of MDR1 have been noted in leukemic blasts with t(8;21).…”

Selective anti-leukaemic activity of low-dose histone deacetylase inhibitor ITF2357 on AML1/ETO-positive cells

“…Core-binding factor (CBF) acute myeloid leukaemia (AML) exhibit gene rearrangements which involve genes encoding CBF subunits, such as AML1 (CBFa2) or CBFb. In particular, the translocation t(8;21; q22;q22), which leads to gene repression via the formation of the AML1/ETO chimaeric gene, may represent a paradigm for a molecular mechanism of leukaemogenesis (Downing, 1999). In contrast to AML1, which recruits the transcriptional co-activators p300 and CBP endowed with intrinsic histone acetyl transferases (HAT) activity, AML1/ETO recruits, via NCoR/Sin3A, the histone deacetylase 1 (HDAC1), which drives the transcriptional repression of AML1-controlled genes (Ogawa et al, 1993;Ogryzko et al, 1996;Gelmetti et al, 1998;Kitabayashi et al, 1998;Wang et al, 1998).…”

Transcription factors and translocations in lymphoid and myeloid leukemia

“…52,53 It has been shown to be important in transcriptional activation and repression and it has also been implicated in DNA replication, although evidence suggests that the critical target genes have yet to be identified. 54 The ETO gene is located on chromosome 8q22 and encodes the mammalian homologue of the Drosophila protein Nervy. 55 Identification of other ETO family members involved in translocations with AML1 suggests that ETO sequences are critical for the transforming activity of these fusion proteins.…”

“…55 Identification of other ETO family members involved in translocations with AML1 suggests that ETO sequences are critical for the transforming activity of these fusion proteins. 54 Experimental evidence involving interactions between ETO and the nuclear co-repressors N-CoR and Sin3A, which can recruit an active histone deacetylase, suggests that it is likely to function as a regulator of transcription. 56-58 ETO can form homodimers and heterodimers and it is likely that these multisubunit complexes function in transcriptional regulation and the formation of different heterodimers may lead to functional differences in the activity of these complexes.…”

“…56-58 ETO can form homodimers and heterodimers and it is likely that these multisubunit complexes function in transcriptional regulation and the formation of different heterodimers may lead to functional differences in the activity of these complexes. 54 The first genetic rearrangement to be discovered was t(8;21) in patients with a form of acute myelogenous leukemia (AML). 59 The AML1 gene is located at the translocation breakpoint on chromosome 21 in the t(8;21)(q22;q22) translocation (AML1/ETO) 60 and the fusion protein is present in 12% of AML cases.…”