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Blood, Vol. 92 No. 4 (August 15), 1998:
pp. 1125-1130
RAPID COMMUNICATION
ABI-1, a Human Homolog to Mouse Abl-Interactor 1, Fuses the
MLL Gene in Acute Myeloid Leukemia With t(10;11)(p11.2;q23)
By
Tomohiko Taki,
Noriko Shibuya,
Masafumi Taniwaki,
Ryoji Hanada,
Kazuhiro Morishita,
Fumio Bessho,
Masayoshi Yanagisawa, and
Yasuhide Hayashi
From the Department of Pediatrics, Faculty of Medicine, University of
Tokyo, Bunkyo-ku, Tokyo, Japan; the 3rd Department of Internal
Medicine, Kyoto Prefectural University of Medicine,
Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan; the Division of
Hematology/Oncology, Saitama Children's Medical Center, Iwatsuki,
Japan; and the Biology Division, National Cancer Center Research
Institute, Chuo-ku, Tokyo, Japan.
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ABSTRACT |
Recurrent translocation t(10;11) has been reported to be associated
with acute myeloid leukemia (AML). Recently, two types of chimeric
transcripts, MLL-AF10 in t(10;11)(p12;q23) and
CALM-AF10 in t(10;11)(p13;q14), were isolated. t(10;11) is
strongly associated with complex translocations, including
invins(10;11) and inv(11)t(10;11), because the direction of
transcription of AF10 is telomere to centromere. We analyzed a
patient of AML with t(10;11)(p11.2;q23) and identified ABI-1 on
chromosome 10p11.2, a human homolog to mouse Abl-interactor 1 (Abi-1),
fused with MLL. Whereas the ABI-1 gene bears no
homology with the partner genes of MLL previously described,
the ABI-1 protein exhibits sequence similarity to protein of homeotic
genes, contains several polyproline stretches, and includes a
src homology 3 (SH3) domain at the C-terminus that is required
for binding to Abl proteins in mouse Abi-1 protein. Recently, e3B1, an
eps8 SH3 binding protein 1, was also isolated as a human homolog to
mouse Abi-1. Three types of transcripts of ABI-1 gene were
expressed in normal peripheral blood. Although e3B1 was
considered to be a full-length ABI-1, the MLL-ABI-1
fusion transcript in this patient was formed by an alternatively
spliced ABI-1. Others have shown that mouse Abi-1 suppresses
v-ABL transforming activity and that e3B1, full-length ABI-1, regulates
cell growth. In-frame MLL-ABI-1 fusion transcripts combine the
MLL AT-hook motifs and DNA methyltransferase homology region with the
homeodomain homologous region, polyproline stretches, and SH3 domain of
alternatively spliced transcript of ABI-1. Our results suggest
that the ABI-1 gene plays a role in leukemogenesis by
translocating to MLL.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
VARIOUS CHROMOSOMAL translocations
associated with human cancers have been identified and
characterized.1,2 Recurrent translocations involving
chromosome 11 band q23 (11q23) observed in acute leukemia or
myelodysplastic syndrome (MDS) are characterized by the presence of a
variety of partner chromosomes.3 At least 20 chromosomal
regions for partners of 11q23 have been observed, such as t(4;11),
t(9;11) and t(11;19). The MLL gene4 (also called
ALL-1, HRX, and HTRX-1) has been identified in
11q23 translocations,5-7 and its rearrangement was found in
the majority of infant8-10 and secondary
leukemias.11,12 Up to now, 14 partner genes for MLL
have been cloned from leukemia cells with various types of reciprocal
translocations, and they formed fusion transcripts with MLL.
However, it remains to be elucidated whether the MLL gene, the
partner genes, or the fusion transcripts play a critical role in
leukemogenesis.
There has been a series of reports of t(10;11) translocation in acute
leukemia.13-15 Recently, two types of chimeric transcripts, MLL-AF10 in t(10;11)(p12;q23)16 and
CALM-AF10 in t(10;11)(p13;q14),17 were isolated.
Cytogenetic evidence suggests that there is heterogeneity in the
breakpoints on 10p, with 10p11, 10p12, 10p13, 10p14, and 10p15.
However, molecular analysis of these 10;11 translocations has shown
that the AF10 gene at 10p12 is common in these abnormalities. In addition, as compared with other 11q23 translocations involving MLL, t(10;11) is strongly associated with complex
translocations, such as invins(10;11) and inv(11)t(10;11), because the
direction of transcription of AF10 is telomere to
centromere.15,18,19 Because of this opposite orientation,
the t(10;11)(p12;q23) cannot form the regular head to tail fusion
transcripts found in other 11q23 translocations. This may explain why
the t(10;11)(p12;q23) is often complex and associated with 11q
insertions.
Despite the heterogeneity of 10;11 translocations, previous papers
reported only AF10 is involved in various 10;11 translocations. We identified here another gene, ABI-1, which is fused to
MLL, in a patient of t(10;11)(p11.2;q23)-acute myeloid leukemia
(AML). The ABI-1 is a human homolog to mouse Abl-interactor 1 (Abi-1), encoding an Abl-binding protein.20 The
ABI-1 is the second partner gene located on chromosome 10p,
suggesting that heterogeneity of 10;11 translocation is due to the
presence of ABI-1 gene. These findings may help to clarify the
mechanisms underlying chromosomal aberrations and leukemogenesis in
leukemias with 11q23 abnormalities.
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MATERIALS AND METHODS |
Patient.
An 8-month-old boy was diagnosed as having acute myelomonocytic
leukemia (AMMoL; French-American-British [FAB] M4), which was
cytogenetically characterized as t(10;11)(p11;q23). He was treated by
intensive chemotherapy followed by autologous bone marrow
transplantation and has been in complete remission for 5 years.
Southern blot analysis.
High molecular weight DNA was extracted from bone marrow cells from the
patient by proteinase K digestion and phenol/chloroform extraction. Ten
micrograms of DNA was digested with appropriate restriction enzymes,
subjected to electrophoresis on 0.8% agarose gels, transferred to
charged nylon filters (Amersham, Buckinghamshire, UK), and
hybridized to DNA probes labeled by the random hexamer method.21 A 0.9-kb BamHI fragment (designated probe
x) derived from MLL cDNA22 was used as a probe.
Preparation of mRNA and cDNA libraries.
Poly(A)+ RNA from frozen cells was extracted with a Fast
Track mRNA Isolation Kit (Invitrogen, San Diego, CA). A cDNA library was constructed with poly(A) selected mRNA from patient cells and
BALM14 cell line following established procedures.23
Briefly, random hexanucleotide-primed synthesized cDNAs were ligated
with EcoRI adaptors, and cloned into the EcoRI-digested
 gt10 cloning vector (Promega, Madison, WI). After packaging with
commercial packaging kits (Epicentre Technologies, Madison, WI), phage
plaques were screened with probes labeled using a random primer
synthesis kit (Stratagene, La Jolla, CA). The probe x for the patient
cDNA library and the 320-bp ABI-1 cDNA probe derived from
MLL-ABI-1 chimeric clone for the BALM 14 cDNA library were used
for screening.
Reverse transcriptase-polymerase chain reaction (RT-PCR).
Total cellular RNA was extracted from bone marrow cells of the patient
by the acid guanidine isothiocyanate-phenol-chloroform method.24 Four micrograms of total RNA was reverse
transcribed to cDNA in a total volume of 20 µL with random hexamers
and 20 U of reverse transcriptase (AMV; Boehringer Mannheim, Mannheim, Germany). One twentieth of the cDNA was amplified by PCR in a total
volume of 100 µL with 50 mmol/L KCl, 1.5 mmol/L MgCl2, 10 mmol/L Tris-HCl (pH 9.0 at room temperature), 25 pmol of each primer,
75 µmol/L of each dNTP, and 2.5 U of Taq polymerase (Applied Biosystems, Urayasu, Japan). After 30 rounds of PCR (30 seconds at
94°C, 30 seconds at 55°C, and 1 minute at 72°C), 5 µL of
PCR product was electrophoresed in a 3% agarose gel.25
Primers used were as follows: MLL-7S,
5 -TCCTCAGCACTCTCTCCAAT-3; m-1S,
5-CAGCATAGTCCAGGCAGGA-3; m-1A,
5-GGAGAGTCATCAAACATGGG-3.
Nucleotide sequencing.
PCR products were cloned into the TA cloning vector (Invitrogen).
Nucleotide sequences of phage clones and PCR products were determined
by the fluorometric method (Dye Terminator Cycle Sequencing Kit;
Applied Biosystems).
Northern blot analysis.
Multiple human tissue Northern blots (Clontech, Palo Alto, CA) were
hybridized with 32P-labeled clone 48 as a
probe.23
Fluorescence in situ hybridization (FISH) analysis.
Chromosomal mapping of the genomic clones (H4, H5-2, H7-2, H18, and
H20) was performed by the FISH method.26 The phage clones were labeled by the standard nick translation method using
biotin-16-dUTP (Boehringer Mannheim). To confirm the origin of cloned
DNAs, we also mapped these genomic clones to leukemic cells together
with whole chromosome painting probe for chromosome 10 (WCP10;
Coatasome 10, digoxigenin-labeled; Oncor, Gaithersburg,
MD). We also performed a series of FISH studies on
leukemic samples to further characterize t(10;11) using WCP11
(Coatasome 11, digoxigenin-labeled; Oncor).
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RESULTS |
Rearrangement of MLL and noninvolvement of AF10.
Southern blot analysis of DNA prepared from the leukemic cells of the
patient using probe x showed a chromosomal breakpoint within the
breakpoint cluster region of MLL gene at 11q23
(Fig 1) that spans exons 5 through 11 in
the MLL locus.22 However, no PCR products were
amplified from the cDNA prepared from these cells when MLL-AF10
specific primer pair was used. We inferred that the MLL in this
patient is fused to a novel partner gene.
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| Fig 1.
Southern blot of DNA digested with HindIII and
probed with the 0.9-kb fragment of the MLL gene. C, normal
peripheral lymphocytes. P, leukemic cells from the patient. The patient
exhibited a rearranged band (arrowhead) with this probe.
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Isolation of the MLL fusion cDNAs in t(10;11)(p11;q23).
To isolate fusion transcripts of MLL, we prepared a cDNA
library from mRNA of the patient's leukemic cells. Four cDNA clones were isolated by screening with probe x, and one (clone 15-21) of them
was found to represent a fusion transcript of MLL. Clone 15-21, 682 bp in size, contained a 362-bp sequence corresponding to exons 5 to
7 in the MLL gene at the 5 region, and the remaining 320-bp sequence did not match the MLL gene or the partner genes of MLL previously cloned (Fig 2A).
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| Fig 2.
(A) Partial sequences of MLL-ABI-1 chimeric
transcript. Vertical lines indicate the exon-exon junctions of each
gene. Arrowheads indicate the fusion points of each cDNA. (B) ABI-1
cDNA clones (B48, B30) and e3B1. AAAAA, poly(A) tail. (C) Comparison
among three types of ABI-1 (e3B1, B48, and B30) predicted amino acid sequence.
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Isolation of the ABI-1 gene.
The 320-bp sequence identified in the chimeric clone was used as a
probe to screen a cDNA library from the BALM14 cell line. We isolated
two kinds of clones. Clones B30 and B48 contained sequences of 2,920 and 2,195 nucleotides with an open reading frame, encoding a protein of
387 (42.7 kD) and 447 (48.8 kD) amino acids, respectively (Fig 2B).
Both clones include a poly(A) tail. Between these two clones, there are
two sequence differences (Fig 2B and C). Based on the sequence
analysis, a 177-bp stretch was inserted in the middle of the coding
region in clone B48, whereas a 1,121-bp sequence in the 3
untranslated region was shortened in clone B48. The entire amino acid
sequence exhibits high similarity (81.5%) to mouse Abi-1, a SH3
protein that suppresses v-abl transforming activity by binding to the
Abl protein,20 suggesting that the protein is a human
homolog to mouse Abi-1. Therefore, we designated these clones as ABI-1.
ABI-1 has no significant similarity to other MLL
partner genes reported previously, except for the SH3 domain of EEN.
Recently, another group isolated an eps827 SH3 binding
protein 1, e3B1,28 as a human homolog to mouse Abi-1. The
amino acid (nucleotide) sequence of ABI-1 completely matched that of
e3B1 except in two regions, an additional 5 amino acids stretch (region
A in Fig 2B and C) and 29 amino acids stretch (region B1 in Fig 2B and
C). Region A (residues 155 to 159 in e3B1) occurs after the homeodomain
homologous region, which is homologous to the DNA-binding sequence of
homeodomain proteins. Region B1 (residues 333 to 361 in e3B1) occurs
just before the polyproline stretches, but both regions are located
after the chromosomal breakpoint of t(10;11). Region B2 (residues 274 to 361 in e3B1) lacking in clone 30 included a part of the homeodomain homologous region (the second PEST domain in e3B1) and region B1.
Expression of the ABI-1 gene in normal tissues.
To examine for expression of the ABI-1 gene, we performed
Northern blot analysis on poly(A)-selected RNA from various human tissues. The expressions of the 2.4- and 3.2-kb transcripts appeared constant in most tissues examined (Fig 3).
Clone B48 of the ABI-1 cDNA obtained encompasses approximately
2,195 nucleotides and most likely corresponds to the 2.4-kb transcript.
On the other hand, the 3.2-kb transcript may be the product of clone
B30 and full-length ABI-1, e3B1. Furthermore, we performed
RT-PCR analysis for RNAs from normal peripheral blood using primers
m-1S and m-1A and detected two major transcripts and an extremely weak
expression of the largest sized transcript in all cells
(Fig 4). Sequence analysis showed that the
two major products correspond to clones B48 and B30, respectively, and
that the largest sized band corresponds to e3B1, suggesting
that the alternatively spliced transcripts of ABI-1, clones B48
and B30, are major transcripts of ABI-1 in normal peripheral
blood.
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| Fig 3.
Northern blot analysis of RNAs from adult (A) and fetal
(B) human tissues. ABI-1 cDNA fragment was used as a probe for
the Northern blots in the upper figures. Membranes were rehybridized to
the  -actin probe for the lower figures. Names of the organs are
indicated on top of the figures.
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| Fig 4.
Expression of the ABI-1 in normal peripheral
blood by RT-PCR analysis. Total RNAs isolated from peripheral blood of
8 healthy volunteers were used as the cDNA template. M, size marker
(1-kb DNA ladder; GIBCO BRL, Gaithersburg, MD). Arrows indicate the amplified bands.
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MLL-ABI-1 fusion transcript is formed by alternatively spliced
transcript of ABI-1.
To clarify the expression of MLL-ABI-1 fusion transcript in the
patient's leukemic cells, we performed RT-PCR analysis for RNA from
leukemic cells using primers MLL-7S and m-1A that could detect regions
A, B1, and B2, absent in clones B48 or B30, and detected only about a
1.0-kb band (data not shown). The amplified fragment was cloned into TA
cloning vector and sequence analysis showed that it was formed of the
fusion transcript of ABI-1 that lacked regions A and B1, as
observed in clone B48. In clone 15-21 of chimeric MLL-ABI-1
transcript isolated from the patient's leukemic cells, a portion of
ABI-1 with 320 bp in the fusion cDNA fragment also lacked
region A. These findings suggest that MLL-ABI-1 fusion transcript is formed by alternatively spliced transcript of
ABI-1, corresponding to clone B48. On the other hand, when we
used reciprocal primers for identifying an ABI-1/MLL fusion
transcript, no PCR products were obtained.
Assignment of the ABI-1 gene.
To assign a chromosomal localization for the ABI-1 gene, we
obtained 6 phage clones (H4, H5-2, H7-2, H18, H20, and H7-3) after screening of a genomic library from human placental DNA using clone B48
as a probe. All phage clones were assigned to band 10p11.2 on normal
metaphase chromosomes by FISH analysis (data not shown). Because
multiple phage clones mapped to only one chromosomal locus, it is also
suggested that ABI-1 (B30 and B48) and e3BI are
alternatively spliced transcripts of a single gene.
Precise chromosome analysis of leukemic cells by FISH.
FISH analysis on patient's metaphase chromosomes using human genomic
DNA clones spanning the ABI-1 gene showed that five (H4, H5-2,
H7-2, H18, and H20) of the clones containing the 5 end of the
breakpoint of the ABI-1 gene hybridized to der(10) and one
(H7-3) containing the 3 end to der(11) in leukemic cells (data
not shown). Furthermore, we performed FISH analysis on U937 cell line,
in which AF10 on 10p12 translocated to CALM on
11q14,17 and showed that all phage clones of ABI-1
hybridized to der(10) but not der(11) (data not shown). These results
suggest that the ABI-1 gene is disrupted in
t(10;11)(p11.2;q23)-AMMoL and that the breakpoint is located
centromeric to the AF10 gene.
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DISCUSSION |
Two types of t(10;11) have been identified: t(10;11)(p12;q23), which
creates the MLL-AF10 fusion gene,16 and
t(10;11)(p13;q14), which creates CALM-AF10 fusion
gene.17 In the present study, we isolated a novel chimeric
transcript, MLL-ABI-1, in a patient of AMMoL with
t(10;11)(p11.2;q23). FISH analysis shows that ABI-1 gene is
located centromeric to the AF10 gene. At the cytogenetic level,
it may be difficult to distinguish MLL-ABI-1 and
MLL-AF10 fusions, and it is likely that other cases of t(10;11)
may result in this gene fusion. Recent molecular analysis showed that
ENL,5 ELL29/MEN,30 and
EEN31 genes in the same chromosomal region, 19p13,
were partner genes of MLL with t(11;19)(q23;p13), respectively.
That no amplified product was detected by RT-PCR may be due not only to
the heterogeneity of the breakpoints of the same gene, but also to the
different partner genes.
ABI-1, a human homolog to mouse Abi-1,20 has high homology
to ABI-2.32 These proteins exhibit sequence similarity to
homeotic genes and contain several polyproline stretches and an SH3
domain at the C-terminus. Although EEN, a partner gene for MLL,
also has an SH3 domain, the remaining region of EEN does not have any homology to ABI-1.31 The e3B1, which showed full-length
ABI-1, was isolated as an eps8 binding protein.28 eps8 is a
substrate of receptor tyrosine kinases and is an SH3 domain containing
protein that plays an important role in mitogenic
signaling.27 e3B1 is considered to be a downstream target
for eps8. Overexpression of e3B1 inhibits cell growth, suggesting that
e3B1 is associated with regulation of cell proliferation. On the other
hand, the mouse Abi-1 protein was isolated as an ABL-binding protein
that suppresses v-ABL transforming activity.20 Similarly,
ABI-2 was isolated as another ABL-binding protein that interacts with
c-ABL through both the SH3 domain and C-terminus of the c-ABL and
modulates c-ABL transforming activity.32 The c-ABL protein,
originally identified as the cellular homolog of the v-abl oncogene
product of Abelson murine leukemia virus, is a tyrosine kinase. c-ABL is closely associated with leukemogenesis of chronic myelogenous leukemia and acute lymphoblastic leukemia (ALL) creating
BCR-ABL fusion transcript in t(9;22)(q34;q11). Although it was
suggested that both Abi-1 and ABI-2 are regulators of ABL function in
transformation or in signal transduction, the functional correlation
between Abi-1, ABI-2, and BCR-ABL is still unknown. Furthermore, it is not known whether the function of alternatively spliced transcripts of
ABI-1, clones B30 and B48, is the same as that of e3B1 or
Abi-1.
The MLL gene is fused to various partner genes by 11q23
chromosomal translocations. Up to now, 14 partner genes for MLL
have been cloned from leukemia cells with various types of reciprocal translocations, including t(4;11), t(9;11), and t(11;19). They include
the putative transcriptional factors (AF4, AF9, AF10, AF17, and ENL), a
target gene for Ras (AF6),33 and an RNA polymerase II
elongation factor (ELL).34 Furthermore, transcriptional
coactivators and/or histone acetyltransferases, CBP and p300,
were shown to be novel partner genes for MLL in therapy-related AML
(MDS) with t(11;16) and t(11;22), respectively by us35,36
and others.37,38 The functions of the normal MLL
gene and the fusion transcripts have remained unknown. Two studies
reported that chimeric mice carrying the mouse Mll-AF9 fusion
gene developed AML39 and that hematopoietic progenitor
cells transduced with HRX(MLL)-ENL induced AML in vitro,40
respectively. Rearrangements of the MLL gene found in ALL, AML,
and MDS suggest that this gene fused to various partner genes plays a
causative role in the dysregulation of differentiation along both
lymphoid and myeloid pathways.
A schematic representation of the predicted MLL-ABI-1 fusion proteins
is shown in Fig 5, with the predicted
MLL-ABI-1 fusion transcripts encoding a protein of 1,727 aa containing
1,406 aa from MLL in the N-terminus and 321 aa from ABI-1 in the
C-terminus. The MLL-ABI-1 chimeric protein retains the AT-hook domain,
DNA methyltransferase homology region, and a transcriptional repression domain of MLL, and the homeodomain homologous region and the
SH3 domain of ABI-1. Although e3B1 was reported to be a cytosolic protein,28 many partner genes of MLL encode nuclear
proteins, suggesting that ABI-1 is a cytosolic protein; MLL-ABI-1
chimeric product may localize in the nuclei similar to MLL-AF6 despite the fact that AF6 itself localizes in the
cytosol.41 Because ABI-1 is suggested to
function as a tumor suppressor, one of the mechanisms of leukemogenesis
by the MLL-ABI-1 fusion may be that the function of normal ABI-1 is
dominantly suppressed by the fusion protein. One report suggested that
gain-of-function by creating chimeric transcripts involving MLL
induced transforming activity.42 These findings suggest
that not only dysfunction of normal ABI-1, but also gain-of-function by
fusion of MLL and ABI-1 is necessary to induce
leukemogenesis. Further functional analysis of the MLL-ABI-1 fusion gene will provide new insights into leukemogenesis by 11q23 chromosomal translocations.
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| Fig 5.
Schematic representation of the MLL, ABI-1, and MLL-ABI-1
fusion proteins. MT, DNA methyltransferase homology region; TRX, Drosophila trithorax. HHR, homeodomain homologous region.
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FOOTNOTES |
Submitted March 8, 1998;
accepted May 28, 1998.
Supported by a Grant-in-Aid for Cancer Research from the Ministry of
Health and Welfare of Japan, a Grant-in-Aid for Scientific Research on
Priority Areas, and Grant-in-Aid for Scientific Research (B) and (C)
from the Ministry of Education, Science, Sports and Culture of Japan.
Address reprint requests to Yasuhide Hayashi, MD, Department of
Pediatrics, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113, Japan.
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.
| |
ACKNOWLEDGMENT |
The authors thank M. Seto (Aichi Cancer Center Research Institute) for
providing the MLL cDNA probe (probe x). We also express appreciation to S. Sohma for technical assistance.
| |
REFERENCES |
1.
Rabbitts TH:
Chromosomal translocations in human cancer.
Nature
372:143,
1994[Medline]
[Order article via Infotrieve]
2.
Look AT:
Oncogenic transcription factors in the human acute leukemias.
Science
278:1059,
1997[Abstract/Free Full Text]
3.
Rubnitz JE,
Behm FG,
Downing JR:
11q23 rearrangements in acute leukemia.
Leukemia
10:74,
1996[Medline]
[Order article via Infotrieve]
4.
McCabe NR,
Burnett RC,
Gill HJ,
Thirman MJ,
Mbangkollo D,
Kipiniak M,
van Melle E,
Ziemin-van der Poel S,
Rowley JD,
Diaz MO:
Cloning of cDNAs of the MLL gene that detect DNA rearrangements and altered RNA transcripts in human leukemic cells with 11q23 translocations.
Proc Natl Acad Sci USA
89:11794,
1992[Abstract/Free Full Text]
5.
Tkachuk DC,
Kohler S,
Cleary ML:
Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias.
Cell
71:691,
1992[Medline]
[Order article via Infotrieve]
6.
Gu Y,
Nakamura H,
Alder H,
Prasad R,
Canaani O,
Cimino G,
Croce CM,
Canaani E:
The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene.
Cell
71:701,
1992[Medline]
[Order article via Infotrieve]
7.
Djabali M,
Selleri L,
Parry P,
Bower M,
Young BD,
Evans GA:
A trithorax-like gene is interrupted by chromosome 11q23 translocations in acute leukaemias.
Nat Genet
2:113,
1992[Medline]
[Order article via Infotrieve]
8.
Rubnitz JE,
Link MP,
Shuster JJ,
Carroll AJ,
Hakami N,
Frankel LS,
Pullen DJ,
Cleary ML:
Frequency and prognostic significance of HRX rearrangements in infant acute lymphoblastic leukemia: A Pediatric Oncology Group study.
Blood
84:570,
1994[Abstract/Free Full Text]
9.
Pui C-H,
Kane JR,
Crist WM:
Biology and treatment of infant leukemias.
Leukemia
9:762,
1995[Medline]
[Order article via Infotrieve]
10.
Taki T,
Ida K,
Bessho F,
Hanada R,
Kikuchi A,
Yamamoto K,
Sako M,
Tsuchida M,
Seto M,
Ueda R,
Hayashi Y:
Frequency and clinical significance of the MLL gene rearrangements in infant acute leukemia.
Leukemia
10:1303,
1996[Medline]
[Order article via Infotrieve]
11.
Hunger SP,
Tkachuk DC,
Amylon MD,
Link MP,
Carroll AJ,
Welborn JL,
Willman CL,
Cleary ML:
HRX involvement in de novo and secondary leukemias with diverse chromosome 11q23 abnormalities.
Blood
81:3197,
1993[Abstract/Free Full Text]
12.
Gill Super HJ,
McCabe NR,
Thirman MJ,
Le Beau MM,
Pedersen-Bjergaard J,
Philip P,
Diaz MO,
Rowley JD:
Rearrangements of the MLL gene in therapy-related acute myeloid leukemia in patients previously treated with agents targeting DNA-topoisomerase II.
Blood
82:3705,
1993[Abstract/Free Full Text]
13.
Kaneko Y,
Maseki N,
Takasaki N,
Sakurai M,
Hayashi Y,
Nakazawa S,
Mori T,
Sakurai M,
Takeda T,
Shikano T,
Hiyoshi Y:
Clinical and hematologic characteristics in acute leukemia with 11q23 translocations.
Blood
67:484,
1986[Abstract/Free Full Text]
14.
Thirman MJ,
Gill HJ,
Burnet RC,
Mbangkollo D,
McCabe NR,
Kobayashi H,
Ziemin-van der Poel S,
Kaneko Y,
Morgan R,
Sandberg AA,
Chaganti RSK,
Larson RA,
Le Beau MM,
Diaz MO,
Rowley JD:
Rearrangement of the MLL gene in acute lymphoblastic and acute myeloid leukemias with 11q23 chromosomal translocations.
N Engl J Med
329:909,
1993[Abstract/Free Full Text]
15.
Berger R,
Le Coniat M,
Flexor MA,
Leblanc T:
Translocation t(10;11) involving the MLL gene in acute myeloid leukemia. Importance of fluorescence in situ hybridization (FISH) analysis.
Ann Genet
39:147,
1996[Medline]
[Order article via Infotrieve]
16.
Chaplin T,
Ayton P,
Bernard OA,
Saha V,
Valle VD,
Hillion J,
Gregorini A,
Lillington D,
Berger R,
Young BD:
A novel class of zinc finger/leucine zipper genes identified from the molecular cloning of the t(10;11) translocation in acute leukemia.
Blood
85:1435,
1995[Abstract/Free Full Text]
17.
Dreyling MH,
Martinez-Climent JA,
Zheng M,
Mao J,
Rowley JD,
Bohlander SK:
The t(10;11)(p13;q14) in the U937 cell line results in the fusion of the AF10 gene and CALM, encoding a new member of the AP-3 clathrin assembly protein family.
Proc Natl Acad Sci USA
93:4804,
1996[Abstract/Free Full Text]
18.
Beverloo HB,
Le Coniat M,
Wijsman J,
Lillingston DM,
Bernard O,
de Klein A,
van Wering E,
Welborn J,
Young BD,
Hagemeijer A,
Berger R:
Breakpoint heterogeneity in t(10;11) translocation in AML-M4/M5 resulting in fusion of AF10 and MLL is resolved by fluorescent in situ hybridization analysis.
Cancer Res
55:4220,
1995[Abstract/Free Full Text]
19.
Tanabe S,
Bohlander SK,
Vignon CV,
Espinosa R III,
Zhao N,
Strissel PL,
Zeleznik-Le NJ,
Rowley JD:
AF10 is split by MLL and HEAB, a human homolog to a putative Caenorhabditis elegans ATP/GTP-binding protein in an invins(10;11)(p12;q23q12).
Blood
88:3535,
1996[Abstract/Free Full Text]
20.
Shi Y,
Alin K,
Goff SP:
Abl-interactor-1, a novel SH3 protein binding to the carboxy-terminal portion of the Abl protein, suppress v-abl transforming activity.
Genes Dev
9:2583,
1995[Abstract/Free Full Text]
21. Sambrook J, Fritch EF, Maniatis T: Molecular Cloning: A
Laboratory Manual. Cold Spring Harbor, NY, Cold Spring Harbor Laboratory, 1989
22.
Yamamoto K,
Seto M,
Komatsu H,
Iida S,
Akao Y,
Kojima S,
Kodera Y,
Nakazawa S,
Ariyoshi Y,
Takahashi T,
Ueda R:
Two distinct portions of LTG19/ENL at 19p13 are involved in t(11;19) leukemia.
Oncogene
8:2617,
1993[Medline]
[Order article via Infotrieve]
23.
Taki T,
Hayashi Y,
Taniwaki M,
Seto M,
Ueda R,
Hanada R,
Suzukawa K,
Yokota J,
Morishita K:
Fusion of the MLL gene with two different genes, AF-6 and AF-5 , by a complex translocation involving chromosomes 5, 6, 8, and 11 in infant leukemia.
Oncogene
13:2121,
1996[Medline]
[Order article via Infotrieve]
24.
Chomczynski P,
Sacchi N:
Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.
Anal Biochem
162:156,
1987[Medline]
[Order article via Infotrieve]
25.
Ida K,
Taki T,
Bessho F,
Kobayashi M,
Taira F,
Hanada R,
Yamamoto K,
Okimoto Y,
Seto M,
Ueda R,
Hayashi Y:
Detection of chimeric mRNAs by reverse transcriptase-polymerase chain reaction for diagnosis and monitoring of acute leukemias with 11q23 abnormalities.
Med Pediat Oncol
28:325,
1997[Medline]
[Order article via Infotrieve]
26.
Taniwaki M,
Nishida K,
Ueda Y,
Misawa S,
Nagai M,
Tagawa S,
Yamagami T,
Sugiyama H,
Abe M,
Fukuhara S,
Kashima K:
Interphase and metaphase detection of the breakpoint of 14q32 translocations in B-cell malignancies by double-color fluorescence in situ hybridization.
Blood
85:3223,
1995[Abstract/Free Full Text]
27.
Fazioli F,
Minichiello L,
Matoska V,
Castagnino P,
Miki T,
Wong WT,
Di Fiore PP:
Eps8, a substrate for the epidermal growth factor receptor kinase, enhances EGF-dependent mitogenic signals.
EMBO J
12:3799,
1993[Medline]
[Order article via Infotrieve]
28.
Biesova Z,
Piccoli C,
Wong WT:
Isolation and characterization of e3B1, an eps8 binding protein that regulates cell growth.
Oncogene
14:233,
1997[Medline]
[Order article via Infotrieve]
29.
Thirman MJ,
Levitan DA,
Kobayashi H,
Simon MC,
Rowley JD:
Cloning of ELL, a gene that fuses to MLL in a t(11;19)(q23;p13.1) in acute myeloid leukemia.
Proc Natl Acad Sci USA
91:12110,
1994[Abstract/Free Full Text]
30.
Mitani K,
Kanda Y,
Ogawa S,
Tanaka T,
Inazawa J,
Yazaki Y,
Hirai H:
Cloning of several species of MLL/MEN chimeric cDNAs in myeloid leukemia with t(11;19)(q23;p13.1) translocation.
Blood
85:2017,
1995[Abstract/Free Full Text]
31.
So CW,
Cardas C,
Liu M-M,
Chen S-J,
Huang Q-H,
Gu L-J,
Sham MH,
Wiedermann LM,
Chan LC:
EEN encode for a member of a new family of proteins containing an Src homology 3 domain and is the third gene located on chromosome 19p13 that fuses to MLL in human leukemia.
Proc Natl Acad Sci USA
94:2563,
1997[Abstract/Free Full Text]
32.
Dai Z,
Pendergast AM:
Abi-2, a novel SH3-containing protein interacts with the c-Abl tyrosine kinase and modulates c-Abl transforming activity.
Genes Dev
9:2569,
1995[Abstract/Free Full Text]
33.
Kuriyama M,
Harada N,
Kuroda S,
Yamamoto T,
Nakafuku M,
Iwamatsu A,
Yamamoto D,
Prasad R,
Croce C,
Canaani E,
Kaibuchi K:
Identification of AF-6 and Canoe as putative targets for Ras.
J Biol Chem
271:607,
1996[Abstract/Free Full Text]
34.
Shilatifard A,
Lane WS,
Jackson KW,
Conaway RC,
Conaway JW:
An RNA polymerase II elongation factor encoded by the human ELL gene.
Science
271:1873,
1996[Abstract]
35.
Taki T,
Sako M,
Tsuchida M,
Hayashi Y:
The t(11;16)(q23;p13) translocation in myelodysplastic syndrome fuses the MLL gene to the CBP gene.
Blood
89:3945,
1997[Abstract/Free Full Text]
36.
Ida K,
Kitabayashi I,
Taki T,
Taniwaki M,
Noro K,
Yamamoto M,
Ohki M,
Hayashi Y:
Adenoviral E1A-associated protein p300 is involved in acute myeloid leukemia with t(11;22)(q23;q13).
Blood
90:4699,
1997[Abstract/Free Full Text]
37.
Sobulo OM,
Borrow J,
Tomek R,
Reshmi S,
Harden A,
Schlegelberger B,
Houseman D,
Doggett NA,
Rowley JD,
Zeleznik-Le N:
MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with a t(11;16)(q23;p13.3).
Proc Natl Acad Sci USA
94:8732,
1997[Abstract/Free Full Text]
38.
Satake N,
Ishida Y,
Otoh Y,
Hinohara S,
Kobayashi H,
Sakashita A,
Maseki N,
Kaneko Y:
Novel MLL-CBP fusion transcript in therapy-related chronic myelomonocytic leukemia with a t(11;16)(q23;p13) chromosome translocation.
Genes Chromosom Cancer
20:60,
1997[Medline]
[Order article via Infotrieve]
39.
Corral J,
Lavenir I,
Impey H,
Warren AJ,
Foster A,
Larson TA,
Bell S,
McKerzie ANJ,
King G,
Rabbitts TH:
An Mll-AF9 fusion gene made by homologous recombination causes acute leukemia in chimeric mice: A method to create fusion oncogenes.
Cell
85:853,
1996[Medline]
[Order article via Infotrieve]
40.
Lavau C,
Szilvassy SJ,
Slany R,
Cleary ML:
Immortalization and leukemic transformation of a myelomonocytic precursor by retrovirally transduced HRX-ENL.
EMBO J
16:4226,
1997[Medline]
[Order article via Infotrieve]
41.
Joh T,
Yamamoto K,
Kagami Y,
Kakuda H,
Sato T,
Yamamoto T,
Takahashi T,
Ueda R,
Kaibuchi K,
Seto M:
Chimeric MLL products with a Ras binding cytoplasmic protein AF6 involved in t(6;11) (q27;q23) leukemia localize in the nucleus.
Oncogene
15:1681,
1997[Medline]
[Order article via Infotrieve]
42.
Slany RK,
Lavau C,
Cleary ML:
The oncogenic capacity of HRX-ENL requires the transcriptional transactivation activity of ENL and the DNA binding motifs of HRX.
Mol Cell Biol
18:122,
1998[Abstract/Free Full Text]
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Abstract
Introduction
Abstract