The AML1 gene

A transcription factor involved in the pathogenesis of myeloid and lymphoid leukemias

Francesco Lo Coco, Simona Pisegna, Daniela Diverio

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Background and Objective. The AML1 gene was identified in 1991 by cloning the t(8;21) chromosome translocation associated with FAB M2 acute myeloid leukemia (AML). AML1 encodes a nuclear transcription factor (TF) which shows homology in its 5' part with the Drosophila melanogaster segmentation gene, runt, and contains a transactivation domain in the carboxyterminal portion. In the t(8;21), AML1 is fused to the ETO (MTG8) gene, resulting in a hybrid AML1/ETO mRNA, which in turn is translated into a chimeric protein. The objective of this article is to review here the main structural and biological features of AML1 and of its fusion products, with special focus on their clinical correlations and their potential usefulness for prognostic and monitoring studies in human leukemia. Evidence and Information Sources. The material examined in the present review includes articles and abstracts published in journals covered by the Science Citation Index® and Medline®. State of Art, the normal AML-1 protein forms the α- subunit of the heterodimeric TF core binding factor (or CBF), whose β- subunit is encoded by the CBFβ gene on chromosome 16q22. CBFβ is rearranged and fused to the MYH11 gene in the AML M4Eo-associated inv(16) aberration. Thus, the two most common chromosome abnormalities of AML, i.e. t(8;21) and inv(16), affect the two subunits of the same target protein. This suggests that the wild type CBF must exert an important role in the control of myeloid cell growth and/or differentiation. Evidence that AML1 is a pivotal regulator of definitive hematopoiesis has been recently provided by analyzing AML1 knockout mice. The chromosome region 21q22, where AML1 maps, is involved in several other karyotypic aberrations, such as the t(3;21) translocation associated with a subset of therapy-related myelodysplastic syndromes and AML, and the blast phase of chronic myelogenous leukemia. In this abnormality, three distinct genes: EVI1, EAP, MDS1, located on chromosome band 3q26, have been identified that may recombine with AML1. Finally, the recently cloned t(12;21) translocation has been found to involve the TEL gene (coding for a novel TF) on 12p13, and AML1 on 21q22. This alteration, which results in the production of a TEL/AML1 chimeric protein, is restricted to pediatric B-lineage acute lymphoid leukemia (ALL), where it represents the most frequent molecular defect known to date (up to 25% of cases). Strikingly, the same t(12;21) is identified in only 0.05% of pediatric B- lineage ALL cases analyzed by conventional karyotyping. Other relevant characteristics of TEL/AML1-positive ALL are frequent deletion of the other TEL allele and association with an excellent prognostic outcome. Perspectives. It is expected that future studies will provide more detailed information on the leukemogenic effect of AML1 alterations, and better define the prognostic relevance of detecting the hybrid proteins formed by this gene at diagnosis and during remission.

Original languageEnglish
Pages (from-to)364-370
Number of pages7
JournalHaematologica
Volume82
Issue number3
Publication statusPublished - May 1997

Fingerprint

Lymphoid Leukemia
Myeloid Leukemia
Transcription Factors
Acute Myeloid Leukemia
Genes
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Chromosomes
Core Binding Factor Alpha 2 Subunit
Core Binding Factors
Pediatrics
Blast Crisis
Chromosomes, Human, Pair 21
Karyotyping
Chromosomes, Human, Pair 8
Proteins
Myelodysplastic Syndromes
Hematopoiesis
Protein Subunits
Myeloid Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Keywords

  • AML
  • AML1 gene
  • CML

ASJC Scopus subject areas

  • Hematology

Cite this

The AML1 gene : A transcription factor involved in the pathogenesis of myeloid and lymphoid leukemias. / Lo Coco, Francesco; Pisegna, Simona; Diverio, Daniela.

In: Haematologica, Vol. 82, No. 3, 05.1997, p. 364-370.

Research output: Contribution to journalArticle

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N2 - Background and Objective. The AML1 gene was identified in 1991 by cloning the t(8;21) chromosome translocation associated with FAB M2 acute myeloid leukemia (AML). AML1 encodes a nuclear transcription factor (TF) which shows homology in its 5' part with the Drosophila melanogaster segmentation gene, runt, and contains a transactivation domain in the carboxyterminal portion. In the t(8;21), AML1 is fused to the ETO (MTG8) gene, resulting in a hybrid AML1/ETO mRNA, which in turn is translated into a chimeric protein. The objective of this article is to review here the main structural and biological features of AML1 and of its fusion products, with special focus on their clinical correlations and their potential usefulness for prognostic and monitoring studies in human leukemia. Evidence and Information Sources. The material examined in the present review includes articles and abstracts published in journals covered by the Science Citation Index® and Medline®. State of Art, the normal AML-1 protein forms the α- subunit of the heterodimeric TF core binding factor (or CBF), whose β- subunit is encoded by the CBFβ gene on chromosome 16q22. CBFβ is rearranged and fused to the MYH11 gene in the AML M4Eo-associated inv(16) aberration. Thus, the two most common chromosome abnormalities of AML, i.e. t(8;21) and inv(16), affect the two subunits of the same target protein. This suggests that the wild type CBF must exert an important role in the control of myeloid cell growth and/or differentiation. Evidence that AML1 is a pivotal regulator of definitive hematopoiesis has been recently provided by analyzing AML1 knockout mice. The chromosome region 21q22, where AML1 maps, is involved in several other karyotypic aberrations, such as the t(3;21) translocation associated with a subset of therapy-related myelodysplastic syndromes and AML, and the blast phase of chronic myelogenous leukemia. In this abnormality, three distinct genes: EVI1, EAP, MDS1, located on chromosome band 3q26, have been identified that may recombine with AML1. Finally, the recently cloned t(12;21) translocation has been found to involve the TEL gene (coding for a novel TF) on 12p13, and AML1 on 21q22. This alteration, which results in the production of a TEL/AML1 chimeric protein, is restricted to pediatric B-lineage acute lymphoid leukemia (ALL), where it represents the most frequent molecular defect known to date (up to 25% of cases). Strikingly, the same t(12;21) is identified in only 0.05% of pediatric B- lineage ALL cases analyzed by conventional karyotyping. Other relevant characteristics of TEL/AML1-positive ALL are frequent deletion of the other TEL allele and association with an excellent prognostic outcome. Perspectives. It is expected that future studies will provide more detailed information on the leukemogenic effect of AML1 alterations, and better define the prognostic relevance of detecting the hybrid proteins formed by this gene at diagnosis and during remission.

AB - Background and Objective. The AML1 gene was identified in 1991 by cloning the t(8;21) chromosome translocation associated with FAB M2 acute myeloid leukemia (AML). AML1 encodes a nuclear transcription factor (TF) which shows homology in its 5' part with the Drosophila melanogaster segmentation gene, runt, and contains a transactivation domain in the carboxyterminal portion. In the t(8;21), AML1 is fused to the ETO (MTG8) gene, resulting in a hybrid AML1/ETO mRNA, which in turn is translated into a chimeric protein. The objective of this article is to review here the main structural and biological features of AML1 and of its fusion products, with special focus on their clinical correlations and their potential usefulness for prognostic and monitoring studies in human leukemia. Evidence and Information Sources. The material examined in the present review includes articles and abstracts published in journals covered by the Science Citation Index® and Medline®. State of Art, the normal AML-1 protein forms the α- subunit of the heterodimeric TF core binding factor (or CBF), whose β- subunit is encoded by the CBFβ gene on chromosome 16q22. CBFβ is rearranged and fused to the MYH11 gene in the AML M4Eo-associated inv(16) aberration. Thus, the two most common chromosome abnormalities of AML, i.e. t(8;21) and inv(16), affect the two subunits of the same target protein. This suggests that the wild type CBF must exert an important role in the control of myeloid cell growth and/or differentiation. Evidence that AML1 is a pivotal regulator of definitive hematopoiesis has been recently provided by analyzing AML1 knockout mice. The chromosome region 21q22, where AML1 maps, is involved in several other karyotypic aberrations, such as the t(3;21) translocation associated with a subset of therapy-related myelodysplastic syndromes and AML, and the blast phase of chronic myelogenous leukemia. In this abnormality, three distinct genes: EVI1, EAP, MDS1, located on chromosome band 3q26, have been identified that may recombine with AML1. Finally, the recently cloned t(12;21) translocation has been found to involve the TEL gene (coding for a novel TF) on 12p13, and AML1 on 21q22. This alteration, which results in the production of a TEL/AML1 chimeric protein, is restricted to pediatric B-lineage acute lymphoid leukemia (ALL), where it represents the most frequent molecular defect known to date (up to 25% of cases). Strikingly, the same t(12;21) is identified in only 0.05% of pediatric B- lineage ALL cases analyzed by conventional karyotyping. Other relevant characteristics of TEL/AML1-positive ALL are frequent deletion of the other TEL allele and association with an excellent prognostic outcome. Perspectives. It is expected that future studies will provide more detailed information on the leukemogenic effect of AML1 alterations, and better define the prognostic relevance of detecting the hybrid proteins formed by this gene at diagnosis and during remission.

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