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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 9 (May 1), 1998:
pp. 3127-3133
A Novel Fusion Between MOZ and the Nuclear Receptor
Coactivator TIF2 in Acute Myeloid Leukemia
By
Melina Carapeti,
Ricardo C.T. Aguiar,
John M. Goldman, and
Nicholas C.P. Cross
From the Department of Haematology, Imperial College School of
Medicine, Hammersmith Hospital, London, UK; and the Division of
Hematologic Malignancies, Dana Farber Cancer Institute, Boston, MA.
 |
ABSTRACT |
Chromosomal abnormalities of band 8p11 are associated with a
distinct subtype of acute myeloid leukemia with French-American-British M4/5 morphology and prominent erythrophagocytosis by the blast cells.
This subtype is usually associated with the t(8;16)(p11;p13), a
translocation that has recently been shown to result in a fusion between the MOZ and CBP genes. We have
cloned the inv(8)(p11q13), an abnormality associated with the same
leukemia phenotype, and found a novel fusion between MOZ and
the nuclear receptor transcriptional coactivator
TIF2/GRIP-1/NCoA-2. This gene has not previously been implicated in the pathogenesis of leukemia or other malignancies. MOZ-TIF2 retains the histone acetyltransferase homology domains of both
proteins and also the CBP binding domain of TIF2. We speculate that the
apparently identical leukemia cell phenotype observed in cases with the
t(8;16) and the inv(8) arises by recruitment of CBP by MOZ-TIF2,
resulting in modulation of the transcriptional activity of target genes
by a mechanism involving abnormal histone acetylation.
| |
INTRODUCTION |
THE CHARACTERIZATION of recurrent
chromosomal abnormalities in leukemia has provided a basis for disease
classification and has helped to define prognosis in individual
patients. Furthermore, the molecular cloning of the genes affected by
these chromosomal changes has considerably advanced our understanding
of the mechanisms of leukemogenesis and has enabled the design of
molecular approaches to diagnosis and monitoring patient response to
treatment.
Translocations involving chromosome band 8p11 are associated with a
distinct subtype of acute myeloid leukemia (AML), with blast cells of a
monocytoid phenotype that have pronounced erythrophagocytic activity.
This subtype is found in approximately 2% of cases of AML with
French-American-British M4 or M5 phenotype and typically found in
association with the t(8;16)(p11;p13),1 but it is also seen
in cases with the t(8;22)(p11;q13), t(8;19)(p11;q13), and
inv(8)(p11q13).2-6 Recently the t(8;16) has been cloned and shown to fuse the MOZ gene at 8p11 to the CBP gene at
16p137; the molecular basis of the three other cytogenetic
variants is unknown. Translocations of 8p11 are also observed in the
8p11 myeloproliferative syndrome, a rare disorder associated with the t(8;13)(p11;q12), t(8;9)(p11;q32), and t(6;8)(q27;p11).8
However, the breakpoints in the t(8;13) are distinct from those
associated with de novo AML and do not involve the MOZ
gene.5
Both MOZ and CBP have been implicated in histone
acetylation,7,9-10 suggesting that the mechanism of
leukemogenesis in patients with the t(8;16) involves specific
alterations in gene expression by aberrant chromatin remodelling.
CBP is also disrupted in the t(11;16), a translocation
associated with therapy-related leukemia, by fusion to the MLL
gene.11-12 In this paper we show that the inv(8)(p11q13)
results in a fusion of MOZ to the nuclear receptor coactivator
TIF2/GRIP-1/NCoA-2 (transcriptional intermediary factor 2, hereafter referred to as TIF2),13-15 and propose a
model to explain the similar leukemia phenotypes observed in patients
with the t(8;16) and inv(8).
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MATERIALS AND METHODS |
Patient material/details.
Details of the patient's clinical course and leukemia morphology have
been described elsewhere.5,6 Briefly, a bone marrow aspirate at presentation was hypercellular, with 98% blasts and prominent erythrophagocytosis; a diagnosis of AML-M5 was made. Cytogenetic analysis revealed an inv(8)(p11q13) in 70% of bone marrow
metaphases.
Genomic cloning.
A genomic library was constructed to clone the 7-kb germline
MOZ and 5.1-kb BglII rearranged
fragments detected by the MOZ 0.9 probe. Patient bone marrow genomic
DNA (0.5 µg) was digested with BglII, ligated to
 ZAP Express arms and packaged with Gigapack III Gold
Packaging Extract according to the manufacturer's instructions (Stratagene, Cambridge, UK). A total of 3.3 × 106
plaque-forming units were screened with MOZ 0.9 and five
positive clones were recovered. Germline and rearranged bands were
distinguished by restriction mapping and one of each was sequenced
(model ABI 373A; Applied Biosystems, Foster City, CA).
Fluorescence in situ hybridization (FISH).
A P1 artificial chromosome (PAC) clone (192D10) was isolated by
screening the gridded human library RPCI1 (obtained from the Medical
Research Council Human Genome Mapping Project (MRC HGMP) Resource
Centre, Hinxton, UK) with the probe UN-1. FISH was performed on
metaphases from phytohemagglutinin-stimulated peripheral blood lymphocytes from a normal individual. Digoxigenin-labeled probes were
prepared by nick translation and detected with sheep antidigoxigenin (Boehringer Mannheim, Lewes, UK), rabbit anti-sheep fluorescein isothiocyanate (FITC; Vector, Bretton, Peterborough, UK), and finally
swine anti-rabbit FITC (Dako, High Wycombe, UK). In addition, a
biotinylated chromosome 8 centromere dye was included (Oncor, Durham,
UK), and detected using Texas Red-Avidin (Vector). Chromosomes were
counterstained with DAPI/antifade (Biovation, Aberdeen, UK). FISH-labeled metaphases were examined using an Olympus Vanox
microscope, equipped with a fluorescence unit, a charge-coupled
device camera, and images captured on SmartCapture
Software (Vysis, Richmond, UK).
Rapid amplification of cDNA ends (RACE)-polymerase
chain reaction (PCR).
One microgram of total patient bone marrow RNA was reverse-transcribed
with primer RCT-A (5 -ATTGGTAGCTCTTGATCNNNNNN-3) using standard
conditions.16 A portion of cDNA was amplified with MOZ-RCO
(5-CCCTAGAGAATACTTCCGTC-3) and a primer made up of the unique
sequence from RCT-A (RC-B; 5-ATTGGTAGCTCTTGATC-3). Hemi-nested amplification was performed with an inner MOZ primer (MOZ-RCI: 5-GGATGTACTCAGGTGTCAGT-3) and RC-B. PCR products were shotgun cloned
into pCR2.1 (Invitrogen, Leeu, The Netherlands), screened with a MOZ probe, and sequenced.
Yeast artificial chromosome (YAC) clones.
A gridded CEPH mega YAC library (obtained from the MRC
HGMP Resource Centre) was screened with probes for the 5 and 3 ends of the published TIF2 cDNA sequence.13 Probes were
amplified from human genomic DNA using the primers TIF2-A
(5-GGCACAGTTGCTGATATGTG-3) and TIF2-B (5-GTCCAAGTTGGTCAGGACAT-3)
for the 5 end of TIF2, and TIF2-C (5-GTGGCCTGCTTAGTAACATG-3)
and TIF2-D (5-GGCTTGATACCAATCGAGCT-3) for the 3 end. The
positions of positive clones were compared with existing chromosome
8 contig maps.17-18 Confirmation that these clones
contained the TIF2 gene was obtained by PCR using the
same primers combinations.
| |
RESULTS |
Southern blotting of patient bone marrow DNA with a MOZ
cDNA probe, MOZ 0.9, that spanned the published t(8;16) breakpoints revealed normal- and abnormal-sized bands after digestion with BglII5 (Fig 1A). A
bacteriophage library was constructed from BglII-digested patient DNA and screened with MOZ 0.9. Two types of clone were recovered, corresponding to the normal 7-kb and rearranged 5.1-kb bands, respectively.
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| Fig 1.
(A) Southern Blot analysis. Genomic DNA from four
controls (lanes 1-4) and the inv(8) patient (lane 5) were digested with BglII (i-iii) or EcoRI (iv-vi) and probed with
MOZ 0.9, MOZ I, and UN-1 as indicated. Germline bands were present in
all samples and an additional band was seen for the patient for all
enzyme/probe combinations except EcoRI/MOZ 0.9. (B) Schematic
representation of the two sequenced bacteriophage clones. The 7-kb
and 5.1-kb BglII fragments were derived from the
germline and rearranged bands, respectively. The last MOZ exon
is shown as a filled box and intron sequence as a line. The positions
of the probes MOZ 0.9, MOZ I, and UN-1 are indicated. The breakpoint in
the 5.1-kb clone coincides with the EcoRI site within the last
exon of MOZ, 47 bp downstream of the MOZ intron-exon
junction.
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Sequence analysis of a 7-kb clone revealed a single large MOZ
exon of 4 kb from position 3746 of the cDNA (Genbank: U47742) to the
BglII site at position 7742. Sequence of a 5.1-kb clone showed
a break near the beginning of this exon within the coding sequence
(position 3793), with 1.1 kb of unique sequence fused to
MOZ (Fig 1B). The single published MOZ breakpoint in a
patient with a t(8;16) also interrupted the same exon, but there was no sequence homology between that breakpoint and the one found here. A
probe derived from the 1.1 kb of unique sequence (UN-1) was used to
isolate a PAC clone which, as expected, mapped to 8q13 as determined by
FISH (Fig 2).
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| Fig 2.
FISH. PAC clone 192D10 was hybridized to normal
lymphocyte metaphases along with a chromosome 8 centromere probe.
Hybridization of the PAC is seen at 8q13.
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Primers were designed from the MOZ cDNA sequence upstream of
the last exon and used for 3 RACE-PCR with RNA extracted from the
patient's bone marrow. In addition to normal MOZ products, clones were isolated in which the penultimate exon of this gene was
fused to novel sequence. A search of the Genbank database showed that
the sequence was derived from the TIF2 gene, a
recently described member of the nuclear receptor transcriptional
coactivator family of proteins.13-15 Nucleotide 3745 of
MOZ was joined to nucleotide 2768 of TIF2 (Genbank:
X97674), resulting in an in-frame fusion (Fig
3A).
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| Fig 3.
(A) Sequence surrounding the MOZ-TIF2 fusion.
Nucleotide 3745 of MOZ was joined to nucleotide 2768 of
TIF2. The underlined sequence indicates the region within
TIF2 that is alternatively spliced in both the normal and
fusion genes. (B) RT-PCR analysis of bone marrow RNA from a normal
individual and the patient with the inv(8). Normal MOZ and
TIF2 transcripts were detected in both samples, the lower
TIF2 band resulting from alternative splicing. The
MOZ-TIF2 fusion was seen only in the patient and reciprocal TIF2-MOZ transcripts were not detected. The identity of all
bands was confirmed by sequencing. M, 123-bp molecular weight marker.
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Because the chromosomal localization of TIF2 had not previously
been determined, we hybridized probes generated from the 5 and 3 ends
of this gene to a gridded CEPH megaYAC library. Several positive clones
were isolated that contained the entire TIF2 gene, including
the YACs 798c3 and 815d1 which have been mapped previously to
8q13.2-3.17
The presence of a novel fusion transcript was confirmed by reverse
transcriptase-PCR using cDNA primers either side of the junction. MOZ-TIF2 was specifically amplified from the
patient's bone marrow RNA, but not from bone marrow RNA extracted from
normal individuals (Fig 3B). Reciprocal TIF2-MOZ transcripts
were not detected. Two MOZ-TIF2 bands were amplified, which, by
sequencing, were found to result from alternative splicing within the
TIF2 moiety (nucleotides 2767-2975). The same alternative
splice was found for TIF2 amplified from both the patient and
normal individual. Rearrangement of the TIF2 gene was confirmed
by Southern blotting. After digestion with BglII, probe UN-1
detected the same-sized rearranged band as MOZ 0.9 (Fig 1A).
Rearrangements were not seen in digests of DNA from normal individuals.
| |
DISCUSSION |
The MOZ gene was isolated as a consequence of its fusion to
CBP by the t(8;16) in AML. Of its structural features, the most significant are a PHD/LAP domain, thought to be involved
in protein-protein interactions,19-20 and a region that is
homologous to a number of lower eukaryotic histone acetyltransferases
(HATs).7 Although the precise function of MOZ is
not known, a related gene in Drosophila, MOF, is required for
dosage compensation, the mechanism which enables male flies with a
single X chromosome to express the same level of X-linked products as
females with two X chromosomes.21 The related yeast genes
SAS2 and YBF2 influence transcriptional silencing and,
taken together, it is likely that MOZ is a chromatin-bound HAT that
modulates the transcription of specific target genes. CBP is a
cointegrator/adaptor that is believed to coordinate the transcriptional
effects of multiple signals from cell surface and nuclear
receptors.22-24 Recently it has been shown that CBP also
has HAT activity.9-10
Nuclear receptors are ligand-inducible transcription factors, which
typically consist of three structural domains: an N-terminus containing
an activation function, AF-1; a DNA-binding domain; and a
ligand-binding C-terminus that contains a second activation function,
AF-2.25 AF-2 mediates transcriptional activation through nuclear receptor coactivators (NRCoAs),26,27 which are
thought to stimulate gene expression by facilitating the assembly of
basal transcription factors into a stable preinitiation
complex.28 Transcriptional interference/squelching
experiments have indicated that NRCoAs are limiting factors in this
process.13 TIF2 was recently shown to be one such
mediator of AF-2 function.13 This protein is homologous to
other NRCoAs, specifically SRC-1 (also known as F-SRC-1 and
NCoA-1),15,29-30 and pCIP (also known as RAC3, ACTR, and
AIB1).15,31-33 Although the functional domains of TIF2 have
not been determined, the related proteins SRC-1/F-SRC-1/NCoA-1 and
ACTR/pCIP/RAC3/AIB1 have HAT activity and also interact directly with
CBP.29,34-36 Therefore, it is likely that NRCoAs mediate transcriptional activation by a mechanism involving extensive chromatin
remodeling. Acetylation of amino termini of core histones allows
nucleosomes to unfold, thus increasing access to transcription factors.37 Conversely, histone deacetylation has been shown to repress transcription, at least in some situations.38
The MOZ-TIF2 fusion retains the LAP finger and HAT homology domains of
MOZ, along with the putative CBP interacting domain (CID) and HAT
domain of TIF2 (Fig 4). The fusion does not
retain the TIF2 PAS/bHLH domain, believed to be involved in DNA binding and protein heterodimerization, or the receptor interacting domain (RID), which mediates the binding of transcriptional coactivators to
nuclear receptors via conserved LXXLL motifs.15,29,39
Therefore, it is unlikely that MOZ-TIF2 is able to interact with any of
the upstream components that normally require TIF2 as a transcriptional intermediary. Instead, the HAT activity of TIF2 may directly modulate or augment the transcriptional activity of genes normally regulated by
MOZ (Fig 5A). Alternatively, the TIF2
moiety may serve as a bridge between MOZ and CBP, and it is the HAT or
other activities of CBP that are relevant to putative leukemogenic
alterations in gene expression (Fig 5B). The latter model is
particularly attractive in view of the striking similarity in cell
phenotypes associated with the MOZ-CBP fusion in the t(8;16) (Fig 5C)
and MOZ-TIF2 in the inv(8). The molecular basis of the two variant translocations t(8;19) and t(8;22) is unknown, but they may result in
analogous mechanisms of leukemogenesis. For example, it has been
postulated that the t(8;22) may involve p300 at 22q13, a gene
that is structurally and functionally closely related to CBP.7 Indeed, it has been shown recently that
p300 is fused to the MLL gene in AML with the
t(11;22)(q23;q13).40
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| Fig 4.
Schematic representation of MOZ, TIF2, and MOZ-TIF2
fusion proteins. Domains are indicated as follows: LAP,
leukemia-associated protein20; HAT, histone
acetyltransferase; M-rich, methionine-rich; CID and RID, putative CBP
and nuclear receptor interacting domains based on homology with
SRC-1.29-30 The MOZ-TIF2 fusion retains the LAP finger and
HAT homology domains of MOZ, along with the CID and HAT domains of
TIF2.
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| Fig 5.
Hypothetical models of the mode of action of the MOZ-TIF2
fusion protein. (A) TIF2 may directly modulate the transcriptional activity of genes normally regulated by MOZ through the addition or
removal of histone acetyl (Ac ) groups by its histone
acetyltransferase (HAT) domain. (B) The TIF2 moiety may serve as a
bridge between MOZ and CBP, and it is the HAT or other activities of
CBP that leads to leukemogenic alterations in gene expression.
Chromatin-associated CBP may be responsive to other cellular signals
such as those mediated by jun, CREB, or STAT proteins.22-24
(C) The MOZ-CBP fusion in the t(8;16),7 which is associated
with a strikingly similar leukemia cell phenotype to that seen in cases
with the inv(8).
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Although TIF2 has not previously been implicated in malignancy,
several sporadic leukemias have been described with translocations or
other structural rearrangements that involve chromosome band 8q13.41 Furthermore, the related gene
AIB1/pCIP/RAC3/ACTR at 20q12 is amplified in breast and ovarian
cancers,33 and, in addition, the ARA70
gene was fused to RET in a case of human thyroid papillary
carcinoma42-43 and TIF1 fused to B-RAF in
the mouse hepatoma-derived oncogene T18.44 Although
ARA70 and TIF1 do not share sequence homology with the TIF2
family of NRCoAs, they are also involved in the ligand-dependent activation function of nuclear receptors.43-44 These
observations suggest that subversion of the mechanisms by which nuclear
receptors modulate gene transcription, including specific acetylation
of histones, is widely involved in malignancy.
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FOOTNOTES |
Submitted January 12, 1998;
accepted February 11, 1998.
Supported by the Leukaemia Research Fund. R.C.T.A. was supported by
CNPq (Conselho Nacional de Desenvolvimento Científico e
Tecnológico-No 200995/94-4), Brazil.
Address reprint requests to Nicholas C.P. Cross, PhD, Dept
of Haematology, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Rd, London, W12 ONN, UK.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
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ACKNOWLEDGMENT |
We thank the MRC HGMP Resource Centre for providing the PAC clones and
CEPH megaYAC clones.
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Abstract
Introduction
Abstract