F. Lococo et al., THE AML1 GENE - A TRANSCRIPTION FACTOR INVOLVED IN THE PATHOGENESIS OF MYELOID AND LYMPHOID LEUKEMIAS, Haematologica, 82(3), 1997, pp. 364-370
Background and Objective. The AML1 gene was identified in 1991 by clon
ing the t(8;21) chromosome translocation associated with FAB M2 acute
myeloid leukemia (AML). AML1 encodes a nuclear transcription factor (T
F) which shows homology in its 5' part with the Drosophila melanogaste
r segmentation gene, runt, and contains a transactivation domain in th
e carboxyterminal portion. In the t(8;21), AML1 is fused to the ETO (M
TG8) gene, resulting in a hybrid AML1/ETO mRNA, which in turn is trans
lated into a chimeric protein. The objective of this article is to rev
iew here the main structural and biological features of AML1 and of it
s fusion products, with special focus on their clinical correlations a
nd their potential usefulness for prognostic and monitoring studies in
human leukemia. Evidence and Information Sources. The material examin
ed in the present review includes articles and abstracts published in
journals covered by the Science Citation index(R) and Medline(R) State
of Art. The normal AML-1 protein forms the alpha-subunit of the heter
odimeric TF core binding factor (or CBF), whose beta-subunit is encode
d by the CBF beta gene on chromosome 16q22. CBF beta 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;2
1) and inv(16), affect the two subunits of the same target protein. Th
is 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 recen
tly provided by analyzing AML1 knockout mice. The chromosome region 21
q22, where AML1 maps, is involved in several other karyotypic aberrati
ons, such as the t(3;21) translocation associated with a subset of the
rapy-related myelodysplastic syndromes and AML, and the blast phase of
chronic myelogenous leukemia. In this abnormality, three distinct gen
es: EVl1, EAP, MDS1, located on chromosome band 3q26, have been identi
fied that may recombine with AML1. Finally, the recently cloned t(12;2
1) 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 ped
iatric B-lineage acute lymphoid leukemia (ALL), where it represents th
e most frequent molecular defect known to date (up to 25% of cases). S
trikingly, the same t(12;21) is identified in only 0.05% of pediatric
B-lineage ALL cases analyzed by conventional karyotyping. Other releva
nt characteristics of TEL/AML1-positive ALL are frequent deletion of t
he other TEL allele and association with an excellent prognostic outco
me. 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 pro
teins formed by this gene at diagnosis and during remission. (C) 1997,
Ferrata Storti Foundation.