Download Gene Section CBFA2T3 (core-binding factor, runt domain, alpha

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
CBFA2T3 (core-binding factor, runt domain, alpha
subunit 2; translocated to, 3)
Anthony J Bais
Department of Haematology and Genetic Pathology, Flinders University, Bedford Park, Adelaide, SA 5042,
Australia
Published in Atlas Database: October 2005
Online updated version: http://AtlasGeneticsOncology.org/Genes/CBFA2T3ID428ch16q24.html
DOI: 10.4267/2042/38287
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2006 Atlas of Genetics and Cytogenetics in Oncology and Haematology
CBFA2T3. Another hypothetical protein FLJ23429
transcribes antisense starting from within the first
alternative intron.
Identity
Hugo: CBFA2T3
Other names: MTG16; MTGR2; ZMYND4
Location: 16q24.3
Local order: telomere; centromeric to CDH15 and
telomeric to GALNS.
Pseudogene
None identified.
Protein
DNA/RNA
Description
Description
ETO proteins are composed of four evolutionarily
conserved domains termed nervy homology regions
(NHR1 to 4) and three proline-serine-threonine (PST)
rich regions. The fourth NHR region is also referred to
as the zinc-finger MYND (zf myeloid-nervy-DEAF-1)
domain.
NHR1 shares significant homology to human TATAbinding protein (TBP)-associated factor 130 (hTAF
130), hTAF 105, Drosophila accessory or activation
factor TAF 110, and is often referred to as the TAF 110
domain.
NHR2 is a small region containing homo and
heterodimerization domains and a hydrophobic heptad
repeat (HHR) unit.
The sequence of NHR3 is unremarkable in homology
and often referred to as the nervy domain.
The C-terminal NHR4 domain exists in numerous
human, murine, Caenorhabditis elegans and Drosophila
proteins, and contains a MYND zinc-finger motif. The
motif is composed of CXXC and two (C-H)XXXC
regions which correspond to cysteine-histidine 'knuckle
structures' that are the basic building blocks of many
zinc-finger proteins. The zinc-finger is common to the
developmental proteins rat programmed cell death (RP8), the human homolog programmed cell death 2
(PDCD2), deformed epidermal autoregulatory factor-1
CBFA2T3 encodes two alternative transcripts,
CBFA2T3A and CBFA2T3B, via the use of alternative
start sites at exons 1A and 1B, respectively.
CBFA2T3A is 4,265-bp in length, composed of 13
exons (1A and 2 to 12) spanning approximately 130-kb
of genomic DNA, and has an ORF of 1,959-bp
encoding a protein of 653 amino acids.
CBFA2T3B is 4,034-bp in length, composed of 12
exons (1B to 12 splicing out exon 3) spanning
approximately 50-kb of genomic DNA, and has an
ORF of 1,701-bp encoding a protein of 567 amino
acids.
Additional CBFA2T3C and CBFA2T3D isoforms have
been identified in leukemic and HEL cell lines.
CBFA2T3C encodes a protein that lacks exons 2 and 3,
and CBFA2T3D is a truncated protein with out-offrame splicing of exon 1A to exon 5.
The CBFA2T3A open-reading-frame (ORF) may
include an additional 177 amino acids beyond the
originally proposed methionine start codon.
The CBFA2T3B isoform contains a high-density 1-kb
CpG island within and five prime to the exon 1B start
site.
A hypothetical protein FLJ26728 located within and
proximal to the CpG island transcribes antisense to
Atlas Genet Cytogenet Oncol Haematol. 2006;10(2)
70
CBFA2T3 (core-binding factor, runt domain, alpha subunit 2; translocated to, 3)
(DEAF-1), suppressin (SPN), BLU or zinc-finger
MYND domain containing 10 (ZMYND10),
adenovirus 5 E1A binding protein (BS69), and CD8
beta opposite (BOP).
reporter gene assays. The presence of a zinc-finger
motif common to developmental proteins suggests that
CBFA2T3 might function in regulating differentiation
and morphogenesis. The RP-8 and human homolog
PDCD2 proteins assume a role in programmed cell
death, a process essential for epithelial turnover.
DEAF-1 is essential for early embryonic dorsal
epidermal, eye and wing development in Drosophila.
BOP encodes a muscle-restricted protein essential for
cardiomyocyte differentiation and morphogenesis.
BLU is a candidate tumor suppressor gene from the
3p21.3 LOH region in many human cancers, and SPN
from rat functions as a potent tumor suppressor of
leukemia, lymphoma and thymoma cells and tumor
cells from the brain, breast, pituitary and adrenal
glands.
CBFA2T3 transcripts of CD34(+) progenitor cells have
been shown to be rapidly reduced by cytokine-induced
differentiation into myeloid or erythroid lineages,
supporting suggestion that CBFA2T3 may function in
hematopoietic differentiation. The CBFA2T3B CpG
island contains several Specificity protein 1 (Sp1),
homeotic, epidermal and insulin growth factor
recognition sites. High conserved binding sites include
GATA-1, CREB, F-1 and PKNOX1.
Expression
CBFA2T3 is widely expressed in B-cells, blood, brain,
breast, cervix, colon, eye, kidney tumor, lymph,
marrow, muscle, pancreas, placenta and tonsil.
CBFA2T3 exists predominantly as 4.5 and 4.2-kb
transcripts along with several other minor RNAs in
heart, brain, placenta, lung, liver, skeletal muscle,
kidney, pancreas, spleen, thymus, prostate, testis,
ovary, small intestine, colon and peripheral blood
leukocyte.
Localisation
All ETO members contain nuclear localization signals
(NLS), some of which may be abrogated through five
prime variations to enable extracellular targeting. For
instance, CBFA2T1 has been detected in the cytoplasm
of Purkinje cells in adult human brain, and both
CBFA2T1 and CBFA2T3B have been detected in the
Golgi apparatus, where they may function as cAMPdependent protein kinase anchoring proteins. The
majority of ETO proteins presumably remain in the
nucleus for transcriptional regulation.
Homology
Function
The human gene CBFA2T3 is a member of the eighttwenty-one (ETO) family of proteins. The human ETO
family consists of the ETO gene, also known as the
myeloid translocation gene 8 (MTG8, CBFA2T1), the
myeloid translocation gene related protein-1 (EHT,
MTGR1, CBFA2T2), and the myeloid translocation
gene 16 (MTG16, MTGR2, ZMYND4, HGNC:1537,
CBFA2T3).
Murine homologs of the ETO family include mETO
(cbfa2t1h), ET0-2 (cbfa2t3h), and cbfa2t2h, the latter
of which is uncharacterised. Chicken cETO and
Drosophila nervy homologs have also been identified.
The ETO protein family members and NHRs are highly
homologous and conserved to each other. The
CBFA2T3A and B isoforms share significant
homology to MTG8 (67 and 75%, respectively) and
MTGR1 (54 and 61%, respectively), and approximately
30% homology to nervy. CBFA2T3 shares 86%
homology to the murine ETO-2 (cbfa2t3h), which in
turn shares 75 and 60% homology to MTG8 and
MTGR1, respectively, suggesting that ETO-2 is the
murine homolog of CBFA2T3. MTG8 is approximately
99, 65 and 30% homologous to murine ETO, MTGR1
and nervy, respectively.
CBFA2T3 has been considered to function as a
transcriptional repressor via interaction with
corepressor complexes.
The CBFA2T3A isoform oligomerizes and drags
MTG8 and MTGR1 to the nucleus, oligomerizes with
RUNX1-MTG16 fusion proteins in the nucleoplasm,
interacts with nuclear HDACs 1 and 3, and when
overexpressed accumulates at the periphery of nucleoli
in characteristic rings. Because clustered arrays of
inactive methylated ribosomal DNA (rDNA) repeats
are also found at the nucleoli periphery, it has been
speculated that CBFAT23A could be involved in
methylation silencing of rDNA in the nucleolus.
The CBFA2T3B isoform has been shown to function in
T lymphocytes as a kinase anchorage protein, and
interact with cyclic nucleotide phosphodiesterases,
suggesting it may function in T cell activation and
inflammatory response. CBFA2T3B has been shown to
function as a transcriptional repressor when tethered to
a GAL4 DNA-binding domain in gene reporter assays,
and inhibit the growth of breast tumor cell lines with
reduced expression when ectopically expressed using
retrovirus.
CBFA2T3 has been found to interact with a novel zinc
finger protein KIA00924 to mediate potent
transcriptional repression as determined by CAT
Atlas Genet Cytogenet Oncol Haematol. 2006;10(2)
Bais AJ
Mutations
Note: None recorded.
71
CBFA2T3 (core-binding factor, runt domain, alpha subunit 2; translocated to, 3)
MTG8. The zinc-finger NHR4 is necessary but not
sufficient for repression and interaction with SMRT
and N-CoR in vitro. The direct physical association of
MTG8 with corepressors is more complex. A 'corerepressor domain' containing NHR2 and the
neighboring amino and carboxy terminal sequences
was defined and found to be the strongest region of
interaction with mSin3a and transcriptional repression.
In the RUNX1-MTG8 translocation product associated
with myeloid malignancies, the transactivation domain
of the RUNX1 gene, which normally binds the
transcriptional coactivators p300-CBP, is replaced by
almost the entire MTG8 protein. The resultant fusion
protein recruits a corepressor complex containing
HDAC activity instead of the coactivators p300 - CBP
to RUNX1 responsive genes giving rise to leukemia.
The repression activity of the MTG8 protein was
demonstrated from a GAL4 DNA binding domain
(DBD) MTG8 fusion construct which mediated strong
repression through multimerized GAL4 binding sites
upstream of a minimal promoter driving a reporter
gene. Consistent with a mechanism involving MTG8
and HDAC corepressor interactions, the repressive
effect of MTG8 was partially overcome with the
addition of the HDAC inhibitor trichostatin A (TSA).
Mutational studies of RUNX1-MTG8 have shown that
NHR4 is responsible for repression of the multidrug
resistance 1 promoter.
MTG8 has also been shown to interact with the
Dentato-rubral and Pallido-luysian atrophy gene
product, atrophin-1, in a yeast two-hybrid assay. Both
Dentato-rubral and Pallido-luysian atrophies are
neurodegenerative disorders caused by expansion of
polyglutamine tracts.
Several other transcriptional repressors have been
shown to interact with MTG8. The promyelocytic
leukemia zinc-finger (PLZF), a transcriptional
repressor found in hematopoietic cells and downregulated during differentiation of myeloid cell lines
was shown to exhibit enhanced repressor activity when
interacting with MTG8 in 293T cells and assayed using
a reporter plasmid containing four copies of a high
affinity PLZF binding site linked to firefly luciferase.
The ability of MTG8 to enhance repression was
abolished upon addition of HDAC inhibitors TSA and
sodium butyrate, suggesting that the MTG8 enhanced
repression by PLZF is also mediated through the
recruitment of HDACs.
The Growth factor independence-1 (Gfi-1), a HDAC
interacting transcriptional repressor found in
hematopoietic cells, was shown in vitro and in vivo to
interact with NHR1 and NHR2 of MTG8. These
interactions together with gene targeting experiments
demonstrating MTG8s involvement in gastrointestinal
development, the well established interactions with
corepressor complexes, and the presence of a zincfinger motif common to numerous developmental
proteins, suggests that ETO family members including
Implicated in
t(16;21)(q24;q22) in therapy related
acute myeloid leukemia (t-AML) →
CBFA2T3/RUNX1
Note: CBFA2T3 or MTG16 was identified by
molecular characterization of a second less common
therapy-related AML translocation involving t(16;21).
Characterization of the t(16;21) demonstrated that
RUNX1-MTG16 fusion transcripts similar to RUNX1ETO were generated.
Abnormal Protein
The RUNX1-MTG8, and to a lesser extent the
RUNX1-MTG16,
fusion
transcripts
of
the
t(8;21)(q22;q22) and t(16;21) events are most
recognized for their ability to function as
transcriptional repressors of genes normally activated
by RUNX1 through their interaction with corepressor
complexes involving N-CoR, mSin3A, SMRT, and
HDACs.
The MTG8 or CBFA2T1 gene is the most studied
member of the ETO family and is additionally
recognized for its ability to function independently as a
nuclear transcriptional repressor through nuclear
corepressor complex interaction. Gene targeting
experiments demonstrating that homozygous mutant
mice with an inactivating insertion of LacZ in exon 2 of
the MTG8 locus resulted in massive gastrointestinal
defects, have also shown that MTG8 and perhaps ETO
family members are essential for gastrointestinal
development.
Multiple NHRs of the ETO family of proteins are
required and cooperate to mediate transcriptional
repression. Most of the proteins that interact with
NHRs have been assigned from studies of RUNX1MTG8 and its interacting proteins. Studies originally
demonstrated that MTG8s NHR2 and NHR4 were
required for AML-MTG8 to inhibit RUNX1 mediated
transcriptional activation and initiated the search for
'corepressor complexes' that bind to these regions.
Several yeast two-hybrid systems using portions of
MTG8 as bait demonstrated that specific portions of
NHR2, NHR3 and NHR4 interact with the human
nuclear receptor co-repressor (HuN-CoR)-mSin3AHDAC1 corepressor complex.
The N-CoR protein was originally described to interact
with DNA-bound nuclear receptors to repress
transcription of target genes through recruitment of
HDAC containing complexes and was latter shown to
form complexes with mammalian Sin3 to alter
chromatin structure and mediate transcriptional
repression via nuclear receptors and oncoregulatory
proteins.
A similar yeast two-hybrid approach also established
that the corepressor silencing mediator of retinoic acid
and thyroid hormone receptors (SMRT) interacts with
Atlas Genet Cytogenet Oncol Haematol. 2006;10(2)
Bais AJ
72
CBFA2T3 (core-binding factor, runt domain, alpha subunit 2; translocated to, 3)
Zhang WD, Hirohashi S, Tsuda H, Shimosato Y, Yokota J,
Terada M, Sugimura T. Frequent loss of heterozygosity on
chromosomes 16 and 4 in human hepatocellular carcinoma.
Jpn J Cancer Res 1990;81:108-111.
CBFA2T3 may play function in regulating cell cycle
transcription during differentiation and proliferation of
specific cell type-lineages, for example hematopoietic
cells as indicated for MTG8.
Miyoshi H, Shimizu K, Kozu T, Maseki N, Kaneko Y, Ohki M.
t(8;21) breakpoints on chromosome 21 in acute myeloid
leukemia are clustered within a limited region of a single gene,
AML1. Proc Natl Acad Sci USA 1991;88:10431-10434.
Loss of heterozygosity (LOH) of 16q22qter in breast cancer, prostate cancer,
and several other cancers
Owens GP, Hahn WE, Cohen JJ. Identification of mRNAs
associated with programmed cell death in immature
thymocytes. Mol Cell Biol 1991;11:4177-4188.
Note: This region is frequently deleted in several
human cancers causing loss of heterozygosity. The
16q24.3
region
including
CBFA2T3
spans
approximately 3-Mb from the marker D16S498 to the
telomere and contains at least two smallest regions of
overlap (SROs). These SROs are most frequently
deleted in early and late stage breast cancer and in
prostate cancer. Loss of normal function of CBFA2T3
may be a key event in the early stage of breast cancer.
LOH on the whole 16q22-qter region is frequently
detected in breast and prostate cancer.
CBFA2T3B is a potential tumor suppressor gene
affected by LOH, aberrant gene expression and
promoter methylation in breast cancer. Quantitative
gene expression analysis of 78 genes in the 16q24.3
region demonstrated that CBFA2T3 was the only gene
with an aberrant expression profile distinctly similar to
the known tumor suppressors SYK and CDKN2A. 68
genes displayed normal expression, six displayed
mildly aberrant expression (DPEP1, CDH15,
Hs.17074, Hs.189419, SLC7A5 and AA994450), one
displayed excessively reduced expression (CA5A), and
two displayed moderately aberrant expression (CYBA
and FBX031). The CBFA2T3B promoter region
displays aberrant hypo and hypermethylation in breast
tumor cell lines and primary breast tumor samples in
correlation with aberrant gene expression.
Disease
16q22-qter LOH is detected in bilateral breast cancer
and ductal lavage, in rare inflammatory breast cancer,
and in several other cancers, including central nervous
system neuroectodermal and primary ependymomas,
colorectal liver metastases, gastric tumor, head and
neck squamous cell carcinoma, hepatocellular
carcinoma, lung tumor, nasopharyngeal tumor, ovarian
tumor, rhabdomyosarcoma, and Wilms' tumor. 16q22qter LOH in ovarian, hepatocellular and particularly
breast and prostate cancers, exhibit similar SROs,
suggesting common molecular pathways are affected.
Sato T, Akiyama F, Sakamoto G, Kasumi F, Nakamura Y.
Accumulation of genetic alterations and progression of primary
breast cancer. Cancer Res 1991;51:5794-5799.
Thomas GA, Raffel C. Loss of heterozygosity on 6q, 16q, and
17p in human central nervous
system
primitive
neuroectodermal tumors. Cancer Res 1991;51:639-643.
Erickson P, Gao J, Chang KS, Look T, Whisenant E, Raimondi
S, Lasher R, Trujillo J, Rowley J, Drabkin H. Identification of
breakpoints in t(8;21) acute myelogenous leukemia and
isolation of a fusion transcript, AML1/ETO, with similarity to
Drosophila segmentation gene, runt. Blood 1992;80:18251831.
Maw MA, Grundy PE, Millow LJ, Eccles MR, Dunn RS, Smith
PJ, Feinberg AP, Law DJ, Paterson MC, Telzerow PE, et al. A
third Wilms' tumor locus on chromosome 16q. Cancer Res
1992;52:3094-3098.
Sakai K, Nagahara H, Abe K, Obata H. Loss of heterozygosity
on chromosome 16 in hepatocellular carcinoma. J
Gastroenterol Hepatol 1992;7:288-292.
Hoey T, Weinzierl RO, Gill G, Chen JL, Dynlacht BD, Tjian R.
Molecular cloning and functional analysis of Drosophila
TAF110 reveal properties expected of coactivators. Cell
1993;72:247-260.
Miyoshi H, Kozu T, Shimizu K, Enomoto K, Maseki N, Kaneko
Y, Kamada N, Ohki M. The t(8;21) translocation in acute
myeloid leukemia results in production of an AML1-MTG8
fusion transcript. EMBO J 1993;12:2715-2721.
Erickson PF, Robinson M, Owens G, Drabkin HA. The ETO
portion of acute myeloid leukemia t(8;21) fusion transcript
encodes a highly evolutionarily conserved, putative
transcription factor. Cancer Res 1994;54:1782-1786.
Schwabe JW, Klug A. Zinc mining for protein domains. Nat
Struct Biol 1994;1:345-349.
Chen JD, Evans RM. A transcriptional co-repressor that
interacts
with
nuclear
hormone
receptors.
Nature
1995;377:454-457.
Feinstein PG, Kornfeld K, Hogness DS, Mann RS.
Identification of homeotic target genes in Drosophila
melanogaster including nervy, a proto-oncogene homologue.
Genetics 1995;140:573-586.
Hörlein AJ, Näär AM, Heinzel T, Torchia J, Gloss B, Kurokawa
R, Ryan A, Kamei Y, Söderström M, Glass CK, et al. Ligandindependent repression by the thyroid hormone receptor
mediated by a nuclear receptor co-repressor. Nature
1995;377:397-404.
References
Hwang I, Gottlieb PD. Bop: a new T-cell-restricted gene
located upstream of and opposite to mouse CD8b.
Immunogenetics 1995;42:353-361.
Carter BS, Ewing CM, Ward WS, Treiger BF, Aalders TW,
Schalken JA, Epstein JI, Isaacs WB. Allelic loss of
chromosomes 16q and 10q in human prostate cancer. Proc
Natl Acad Sci USA 1990;87:8751-8755.
Lenny N, Meyers S, Hiebert SW. Functional domains of the
t(8;21) fusion protein, AML-1/ETO. Oncogene 1995;11:17611769.
Tsuda H, Zhang WD, Shimosato Y, Yokota J, Terada M,
Sugimura T, Miyamura T, Hirohashi S. Allele loss on
chromosome 16 associated with progression of human
hepatocellular carcinoma. Proc Natl Acad Sci USA
1990;87:6791-6794.
Atlas Genet Cytogenet Oncol Haematol. 2006;10(2)
Bais AJ
Meyers S, Hiebert SW. Indirect and direct disruption of
transcriptional regulation in cancer: E2F and AML-1. Crit Rev
Eukaryot Gene Expr 1995;5:365-383.
73
CBFA2T3 (core-binding factor, runt domain, alpha subunit 2; translocated to, 3)
Niwa-Kawakita M, Miyoshi H, Gotoh O, Matsushima Y,
Nishimura M, Shisa H, Ohki M. Cloning and gene mapping of
the mouse homologue of the CBFA2T1 gene associated with
human acute myeloid leukemia. Genomics 1995;29:755-759.
MG, Glass C, Seto E, Hiebert SW. ETO, a target of t(8;21) in
acute leukemia, interacts with the N-CoR and mSin3
corepressors. Mol Cell Biol 1998;18:7176-7184.
Lutterbach B, Sun D, Schuetz J, Hiebert SW. The MYND motif
is required for repression of basal transcription from the
multidrug resistance 1 promoter by the t(8;21) fusion protein.
Mol Cell Biol 1998;18:3604-3611.
Ross CA. When more is less: pathogenesis of glutamine
repeat neurodegenerative diseases. Neuron 1995;15:493-496.
Grimes HL, Chan TO, Zweidler-McKay PA, Tong B, Tsichlis
PN. The Gfi-1 proto-oncoprotein contains a novel
transcriptional repressor domain, SNAG, and inhibits G1 arrest
induced by interleukin-2 withdrawal. Mol Cell Biol
1996;16:6263-6272.
Sacchi N, Tamanini F, Willemsen R, Denis-Donini S, Campiglio
S, Hoogeveen AT. Subcellular localization of the oncoprotein
MTG8 (CDR/ETO) in neural cells. Oncogene 1998;16:26092615.
Gross CT, McGinnis W. DEAF-1, a novel protein that binds an
essential region in a Deformed response element. EMBO J
1996;15:1961-1970.
Sato M, Mori Y, Sakurada A, Fukushige S, Ishikawa Y,
Tsuchiya E, Saito Y, Nukiwa T, Fujimura S, Horii A.
Identification of a 910-kb region of common allelic loss in
chromosome bands 16q24.1-q24.2 in human lung cancer.
Genes Chromosomes Cancer 1998;22:1-8.
Suzuki H, Komiya A, Emi M, Kuramochi H, Shiraishi T, Yatani
R, Shimazaki J. Three distinct commonly deleted regions of
chromosome arm 16q in human primary and metastatic
prostate cancers. Genes Chromosomes Cancer 1996;17:225233.
Wang J, Hoshino T, Redner RL, Kajigaya S, Liu JM. ETO,
fusion partner in t(8;21) acute myeloid leukemia, represses
transcription
by
interaction
with
the
human
NCoR/mSin3/HDAC1 complex. Proc Natl Acad Sci USA
1998;95:10860-10865.
Alland L, Muhle R, Hou H Jr, Potes J, Chin L, Schreiber-Agus
N, DePinho RA. Role for N-CoR and histone deacetylase in
Sin3-mediated transcriptional repression. Nature 1997;387:4955.
Davis JN, Williams BJ, Herron JT, Galiano FJ, Meyers S. ETO2, a new member of the ETO-family of nuclear proteins.
Oncogene 1999;18:1375-1383.
Godfrey TE, Cher ML, Chhabra V, Jensen RH. Allelic
imbalance mapping of chromosome 16 shows two regions of
common deletion in prostate adenocarcinoma. Cancer Genet
Cytogenet 1997;98:36-42.
Mori Y, Matsunaga M, Abe T, Fukushige S, Miura K,
Sunamura M, Shiiba K, Sato M, Nukiwa T, Horii A.
Chromosome band 16q24 is frequently deleted in human
gastric cancer. Br J Cancer 1999;80:556-562.
Heinzel T, Lavinsky RM, Mullen TM, Soderstrom M, Laherty
CD, Torchia J, Yang WM, Brard G, Ngo SD, Davie JR, Seto E,
Eisenman RN, Rose DW, Glass CK, Rosenfeld MG. A complex
containing N-CoR, mSin3 and histone deacetylase mediates
transcriptional repression. Nature 1997;387:43-48.
Wang X, Gleich L, Pavelic ZP, Li YQ, Gale N, Hunt S,
Gluckman JL, Stambrook PJ. Cervical metastases of head and
neck squamous cell carcinoma correlate with loss of
heterozygosity on chromosome 16q. Int J Oncol 1999;14:557561.
Latil A, Cussenot O, Fournier G, Driouch K, Lidereau R. Loss
of heterozygosity at chromosome 16q in prostate
adenocarcinoma: identification of three independent regions.
Cancer Res 1997;57:1058-1062.
Wang J, Saunthararajah Y, Redner RL, Liu JM. Inhibitors of
histone deacetylase relieve ETO-mediated repression and
induce differentiation of AML1-ETO leukemia cells. Cancer
Res 1999;59:2766-2769.
Visser M, Sijmons C, Bras J, Arceci RJ, Godfried M, Valentijn
LJ, Voûte PA, Baas F. Allelotype of pediatric
rhabdomyosarcoma. Oncogene 1997;15:1309-1314.
Akhmanova A, Verkerk T, Langeveld A, Grosveld F, Galjart N.
Characterisation of transcriptionally active and inactive
chromatin domains in neurons. J Cell Sci 2000;113:4463-4474.
Calabi F, Cilli V. CBFA2T1, a gene rearranged in human
leukemia, is a member of a multigene family. Genomics
1998;52:332-341.
Gramantieri L, Trerè D, Pession A, Piscaglia F, Masi L, Gaiani
S, Mazziotti A, Bolondi L. Allelic imbalance on 16q in small,
unifocal hepatocellular carcinoma: correlation with HBV and
HCV infections and cellular proliferation rate. Dig Dis Sci
2000;45:306-311.
Chou YH, Chung KC, Jeng LB, Chen TC, Liaw YF. Frequent
allelic loss on chromosomes 4q and 16q associated with
human hepatocellular carcinoma in Taiwan. Cancer Lett
1998;123:1-6.
Ikonomov OC, Petrov T, Soden K, Shisheva A, Manji HK.
Lithium treatment in ovo: effects on embryonic heart rate,
natural death of ciliary ganglion neurons, and brain expression
of a highly conserved chicken homolog of human MTG8/ETO.
Brain Res Dev Brain Res 2000;123:13-24.
Fracchiolla NS, Colombo G, Finelli P, Maiolo AT, Neri A. EHT,
a new member of the MTG8/ETO gene family, maps on 20q11
region and is deleted in acute myeloid leukemias. Blood
1998;92:3481-3484.
Launonen V, Mannermaa A, Stenbäck F, Kosma VM, Puistola
U, Huusko P, Anttila M, Bloigu R, Saarikoski S, Kauppila A,
Winqvist R. Loss of heterozygosity at chromosomes 3, 6, 8, 11,
16, and 17 in ovarian cancer: correlation to clinicopathological
variables. Cancer Genet Cytogenet 2000;122:49-54.
Gamou T, Kitamura E, Hosoda F, Shimizu K, Shinohara K,
Hayashi Y, Nagase T, Yokoyama Y, Ohki M. The partner gene
of AML1 in t(16;21) myeloid malignancies is a novel member of
the MTG8(ETO) family. Blood 1998;91:4028-4037.
Gelmetti V, Zhang J, Fanelli M, Minucci S, Pelicci PG, Lazar
MA. Aberrant recruitment of the nuclear receptor corepressorhistone deacetylase complex by the acute myeloid leukemia
fusion partner ETO. Mol Cell Biol 1998;18:7185-7191.
Masselink H, Bernards R. The adenovirus E1A binding protein
BS69 is a corepressor of transcription through recruitment of
N-CoR. Oncogene 2000;19:1538-1546.
Melnick A, Carlile GW, McConnell MJ, Polinger A, Hiebert SW,
Licht JD. AML-1/ETO fusion protein is a dominant negative
inhibitor of transcriptional repression by the promyelocytic
leukemia zinc finger protein. Blood 2000;96:3939-3947.
Kitabayashi I, Ida K, Morohoshi F, Yokoyama A, Mitsuhashi N,
Shimizu K, Nomura N, Hayashi Y, Ohki M. The AML1-MTG8
leukemic fusion protein forms a complex with a novel member
of the MTG8(ETO/CDR) family, MTGR1. Mol Cell Biol
1998;18:846-8458.
Pederson JA, LaFollette JW, Gross C, Veraksa A, McGinnis
W, Mahaffey JW. Regulation by homeoproteins: a comparison
of deformed-responsive elements. Genetics 2000;156:677686.
Lutterbach B, Westendorf JJ, Linggi B, Patten A, Moniwa M,
Davie JR, Huynh KD, Bardwell VJ, Lavinsky RM, Rosenfeld
Atlas Genet Cytogenet Oncol Haematol. 2006;10(2)
Bais AJ
74
CBFA2T3 (core-binding factor, runt domain, alpha subunit 2; translocated to, 3)
Wood JD, Nucifora FC Jr, Duan K, Zhang C, Wang J, Kim Y,
Schilling G, Sacchi N, Liu JM, Ross CA. Atrophin-1, the
dentato-rubral and pallido-luysian atrophy gene product,
interacts with ETO/MTG8 in the nuclear matrix and represses
transcription. J Cell Biol 2000;150:939-948.
CBFA2T3 (MTG16) is a putative breast tumour suppressor
from the breast cancer loss of heterozygosity region at
16q24.3. Cancer Res 2002;62:4599-4604.
Lerebours F, Bertheau P, Bieche I, Driouch K, De The H,
Hacene K, Espie M, Marty M, Lidereau R. Evidence of
chromosome regions and gene involvement in inflammatory
breast cancer. Int J Cancer 2002;102:618-622.
Zheng PP, Pang JC, Hui AB, Ng HK. Comparative genomic
hybridization detects losses of chromosomes 22 and 16 as the
most common recurrent genetic alterations in primary
ependymomas. Cancer Genet Cytogenet 2000;122:18-25.
Powell JA, Gardner AE, Bais AJ, Hinze SJ, Baker E, Whitmore
S, Crawford J, Kochetkova M, Spendlove HE, Doggett NA,
Sutherland GR, Callen DF, Kremmidiotis G. Sequencing,
transcript identification, and quantitative gene expression
profiling in the breast cancer loss of heterozygosity region
16q24.3 reveal three potential tumor-suppressor genes.
Genomics 2002;80:303-310.
Amann JM, Nip J, Strom DK, Lutterbach B, Harada H, Lenny
N, Downing JR, Meyers S, Hiebert SW. ETO, a target of t(8;21)
in acute leukemia, makes distinct contacts with multiple histone
deacetylases and binds mSin3A through its oligomerization
domain. Mol Cell Biol 2001;21:6470-6483.
Calabi F, Pannell R, Pavloska G. Gene targeting reveals a
crucial role for MTG8 in the gut. Mol Cell Biol 2001;21:56585666.
Scarr RB, Sharp PA. PDCD2 is a negative regulator of HCF-1
(C1). Oncogene 2002;21:5245-54.
Schillace RV, Andrews SF, Liberty GA, Davey MP, Carr DW.
Identification and characterization of myeloid translocation
gene 16b as a novel a kinase anchoring protein in T
lymphocytes. J Immunol 2002;168:1590-1599.
Costoya JA, Pandolfi PP. The role of promyelocytic leukemia
zinc finger and promyelocytic leukemia in leukemogenesis and
development. Curr Opin Hematol 2001;8:212-217.
Fukuyama T, Sueoka E, Sugio Y, Otsuka T, Niho Y, Akagi K,
Kozu T. MTG8 proto-oncoprotein interacts with the regulatory
subunit of type II cyclic AMP-dependent protein kinase in
lymphocytes. Oncogene 2001;20:6225-6232.
Veraksa A, Kennison J, McGinnis W. DEAF-1 function is
essential for the early embryonic development of Drosophila.
Genesis 2002;33:67-76.
Agathanggelou A, Dallol A, Zöchbauer-Muller S, Morrissey C,
Honorio S, Hesson L, Martinsson T, Fong KM, Kuo MJ, Yuen
PW, Maher ER, Minna JD, Latif F. Epigenetic inactivation of
the candidate 3p21.3 suppressor gene BLU in human cancers.
Oncogene 2003;22:1580-1588.
Heibert SW, Lutterbach B, Durst K, Wang L, Linggi B, Wu S,
Wood L, Amann J, King D, Hou Y. Mechanisms of
transcriptional repression by the t(8;21)-, t(12;21)-, and inv(16)encoded fusion proteins. Cancer Chemother Pharmacol
2001;48:S31-34.
Davis JN, McGhee L, Meyers S. The ETO (MTG8) gene family.
Gene 2003;303:1-10.
Hildebrand D, Tiefenbach J, Heinzel T, Grez M, Maurer AB.
Multiple regions of ETO cooperate in transcriptional repression.
J Biol Chem 2001;276:9889-9895.
Diep CB, Parada LA, Teixeira MR, Eknaes M, Nesland JM,
Johansson B, Lothe RA. Genetic profiling of colorectal cancer
liver metastases by combined comparative genomic
hybridization and G-banding analysis. Genes Chromosomes
Cancer 2003;36:189-197.
Yakicier MC, Legoix P, Vaury C, Gressin L, Tubacher E,
Capron F, Bayer J, Degott C, Balabaud C, Zucman-Rossi J.
Identification of homozygous deletions at chromosome 16q23
in aflatoxin B1 exposed hepatocellular carcinoma. Oncogene
2001;20:5232-5238.
Matsuyama H, Pan Y, Yoshihiro S, Kudren D, Naito K,
Bergerheim US, Ekman P. Clinical significance of chromosome
8p, 10q, and 16q deletions in prostate cancer. Prostate
2003;54:103-111.
Yan J, Fang Y, Liang Q, Huang Y, Zeng Y. Novel
chromosomal alterations detected in primary nasopharyngeal
carcinoma by comparative genomic hybridization. Chin Med J
2001;114:418-421.
McGhee L, Bryan J, Elliott L, Grimes HL, Kazanjian A, Davis
JN, Meyers S. Gfi-1 attaches to the nuclear matrix, associates
with ETO (MTG8) and histone deacetylase proteins, and
represses transcription using a TSA-sensitive mechanism. J
Cell Biochem 2003;89:1005-1018.
Zhang J, Hug BA, Huang EY, Chen CW, Gelmetti V,
Maccarana M, Minucci S, Pelicci PG, Lazar MA.
Oligomerization of ETO is obligatory for corepressor
interaction. Mol Cell Biol 2001;21:156-163.
Safford SD, Goyeau D, Freemerman AJ, Bentley R, Everett
ML, Grundy PE, Skinner MA. Fine mapping of Wilms' tumors
with 16q loss of heterozygosity localizes the putative tumor
suppressor gene to a region of 6.7 megabases. Ann Surg
Oncol 2003;10:136-143.
Ansieau S, Leutz A. The conserved Mynd domain of BS69
binds cellular and oncoviral proteins through a common
PXLXP motif. J Biol Chem 2002;277:4906-4910.
Gottlieb PD, Pierce SA, Sims RJ, Yamagishi H, Weihe EK,
Harriss JV, Maika SD, Kuziel WA, King HL, Olson EN,
Nakagawa O, Srivastava D. Bop encodes a muscle-restricted
protein containing MYND and SET domains and is essential for
cardiac differentiation and morphogenesis. Nat Genet
2002;31:25-32.
Asirvatham AL, Galligan SG, Schillace RV, Davey MP, Vasta
V, Beavo JA, Carr DW. A-kinase anchoring proteins interact
with phosphodiesterases in T lymphocyte cell lines. J Immunol
2004;173:4806-4814.
Bais AJ, Gardner AE, McKenzie OLD, Callen DF, Sutherland
GR, Kremmidiotis G. Aberrant CBFA2T3B gene promoter
methylation in breast tumors. Mol Cancer 2004;3:22.
Hansen LL, Jensen LL, Dimitrakakis C, Michalas S, Gilbert F,
Barber HR, Overgaard J, Arzimanoglou II. Allelic imbalance in
selected chromosomal regions in ovarian cancer. Cancer
Genet Cytogenet 2002;139:1-8.
Ibanez V, Sharma A, Buonamici S, Verma A, Kalakonda S,
Wang J, Kadkol S, Saunthararajah Y. AML1-ETO decreases
ETO-2 (MTG16) interactions with nuclear receptor
corepressor, an effect that impairs granulocyte differentiation.
Cancer Res 2004;64:4547-4554.
Hoogeveen AT, Rossetti S, Stoyanova V, Schonkeren J,
Fenaroli A, Schiaffonati L, van Unen L, Sacchi N. The
transcriptional corepressor MTG16a contains a novel nucleolar
targeting sequence deranged in t (16; 21)-positive myeloid
malignancies. Oncogene 2002;21:6703-6712.
Rossetti S, Hoogeveen AT, Sacchi N. The MTG proteins:
chromatin repression players with a passion for networking.
Genomics 2004;84:1-9.
Kochetkova M, McKenzie OLD, Bais AJ, Martin JM, Secker
GA, Seshadri R, Powell JA, Hinze SJ, Gardner AE, Spendlove
HE, O'Callaghan NJ, Cleton-Jansen A, Cornelisse C, Whitmore
SA, Crawford J, Kremmidiotis G, Sutherland GR, Callen DF.
Atlas Genet Cytogenet Oncol Haematol. 2006;10(2)
Bais AJ
Härkönen P, Kyllönen AP, Nordling S, Vihko P. Loss of
heterozygosity in chromosomal region 16q24.3 associated with
progression of prostate cancer. Prostate 2005;62:267-274.
75
CBFA2T3 (core-binding factor, runt domain, alpha subunit 2; translocated to, 3)
Lindberg SR, Olsson A, Persson AM, Olsson I. The Leukemiaassociated ETO homologues are differently expressed during
hematopoietic differentiation. Exp Hematol 2005;33:189-198.
This article should be referenced as such:
Bais AJ. CBFA2T3 (core-binding factor, runt domain, alpha
subunit 2; translocated to, 3). Atlas Genet Cytogenet Oncol
Haematol.2006;10(2):70-76.
Yonekura Y, Yamamoto D, Okugawa H, Tanaka K, Kamiyama
Y. Loss of heterozygosity in ductal lavage for breast tumor and
the contralateral breast. Oncol Rep 2005;13:739-743.
Atlas Genet Cytogenet Oncol Haematol. 2006;10(2)
Bais AJ
76