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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 8 (October 15), 1998:
pp. 2879-2885
CBFA2(AML1) Translocations With Novel Partner Chromosomes in
Myeloid Leukemias: Association With Prior Therapy
By
Diane Roulston,
Rafael Espinosa III,
Giuseppina Nucifora,
Richard
A. Larson,
Michelle M. Le Beau, and
Janet D. Rowley
From the Section of Hematology/Oncology, Department of Medicine, and
the Cancer Research Center, The University of Chicago Pritzker School
of Medicine, Chicago, IL.
 |
ABSTRACT |
CBFA2(AML1) has emerged as a gene critical in hematopoiesis;
its protein product forms the DNA-binding subunit of the heterodimeric core-binding factor (CBF) that binds to the transcriptional regulatory regions of genes, some of which are active specifically in
hematopoiesis. CBFA2 forms a fusion gene with ETO and
MDS1/EVI1 in translocations in myeloid leukemia and with
ETV6(TEL) in the t(12;21) common in childhood pre-B acute
lymphoblastic leukemia. We have analyzed samples from 30 leukemia
patients who had chromosome rearrangements involving 21q22 by using
fluorescence in situ hybridization (FISH). Our analysis showed that 7 of them involved CBFA2 and new translocation partners. Two
patients had a t(17;21)(q11.2;q22), whereas the other 5 had
translocations involving 1p36, 5q13, 12q24, 14q22, or 15q22. Five of
these novel breakpoints in CBFA2 occurred in intron 6; this
same intron is involved in the t(3;21). One breakpoint mapped to the
t(8;21) breakpoint region in intron 5, and 1 mapped 5 to that
region. All 7 CBFA2 rearrangements resulted from balanced translocations. All 7 patients had myeloid disorders (acute myeloid leukemia or myelodysplastic syndrome); 2 were de novo and 5 had treatment histories that included topoisomerase II targeting agents. The association of therapy-related disorders with translocations involving CBFA2 was significant by Fisher's exact test
(P < .003). These results provide further evidence that this
region of CBFA2 is susceptible to breakage in cells exposed to
topoisomerase II inhibitors.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
RECURRING CHROMOSOME translocations often
are specifically associated with particular subtypes of acute myeloid
leukemia (AML) and myelodysplastic syndrome (MDS). The 8;21
translocation, t(8;21)(q22;q22), is one of the most common
rearrangements found in AML and is associated with
French-American-British (FAB) subtype M2 (AML-M2), often with a unique
t(8;21) phenotype.1,2 The translocation fuses the 5
part of CBFA2(AML1) on chromosome 21 and nearly the entire gene
ETO(MTG8) on chromosome 8.3,4 The fusion gene is
oriented such that transcription proceeds from the telomeric (5)
end toward the centromere (reviewed in Nucifora and
Rowley5).
CBFA2 also contributes 5 sequences to fusion genes
produced by the 3;21 translocation.6 The t(3;21) is
associated with therapy-related AML and MDS (t-AML/t-MDS)7
and with chronic myelogenous leukemia in blast crisis
(CML-BC),8 but it is rarely found in AML de
novo.9 The t-AML patients with the t(3;21) often were
treated with topoisomerase II-targeting agents for their primary
malignancies.10-12 The t(3;21) fuses the 5 region of
CBFA2 with up to three different genes (EAP,
MDS1, and EVI1) located over a region of 400 to 750 kb
through remarkable alternative splicing.13 The t(3;21)
breakpoints are located about 60 kb downstream of the t(8;21)
breakpoint region, such that an additional CBFA2 exon (exon 6)
is present in the t(3;21) fusion message
(Fig 1).6
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| Fig 1.
BamHI restriction map of CBFA2 on
chromosome 21 in the region containing the breakpoints of the t(8;21),
t(3;21) and newly identified translocations involving CBFA2
(vertical arrows). The breakpoint region for the t(12;21)(p13;q22)
associated with childhood B-cell ALL is located 5 of the map
area. The numbered vertical bars above the line represent exons and the
vertical lines below the line indicate BamHI sites. The
direction of transcription is indicated by a horizontal arrow. The
recombinant phage walking clones 13 through wc-10 are indicated
by horizontal lines below the map. wc-10 was not precisely mapped and
is indicated by a dashed line. Genomic regions indicated by a dashed
line have not been precisely mapped.
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The t(12;21)(p13;q22) was identified by fluorescence in situ
hybridization (FISH) analysis with whole chromosome painting probes for
chromosome 12 in 3 of 8 patients with acute lymphoblastic leukemia
(ALL); the breakpoint on 21q was localized by using chromosome 21-specific painting probes and yeast artificial chromosomes (YACs) for
that region.14 A fusion gene for
TEL/AML1(ETV6/CBFA2), from 12p13 was cloned.15-17
In contrast to the fusion genes produced in the t(8;21) and t(3;21),
the promoter and 5 sequences in this fusion are provided by
ETV6, and the 3 sequences include almost the entire
CBFA2 gene, including the runt homology domain.
Moreover, all of these patients had B-precursor ALL (CD10+,
CD19+). The t(12;21) has been shown to occur in about 25%
of childhood B-cell ALL and appears to be associated with a good
prognosis.18,19
CBFA2(AML1) shows homology to the Drosophila
segmentation gene runt, which has a DNA-binding region as well
as a domain for protein-protein interaction. The AML1/ETO
fusion gene in the t(8;21)4 as well as the fusion genes
formed by the t(3;21) (AML1/EAP, AML1/EVI1, and
AML1/MDS) include the runt domain.6 Further
downstream, CBFA2 has a transactivation domain. CBFA2 forms a
heterodimer with the subunit CBFB, which confers a greater DNA-binding
activity. Remarkably, CBFB is rearranged by the inv(16)
associated with AML-M4Eo, producing a fusion gene
CBFB/MYH11.20 Significantly, CBFA2 has a
large number of splice variants in both the 5 and 3
regions, and at least two promoters (two 5UTRs) have been identified.21 Mouse homologs have also been identified;
mice with homozygous mutations in CBFA2 are deficient in
hematopoiesis and die during embryonic development.22,23
We asked whether translocations involving 21q22 and other chromosome
partners would show breaks within the CBFA2 gene, in a manner
similar to the large number of partner chromosomes that produce fusion
genes with 5 sequences derived from MLL on chromosome 11 band q23 (reviewed in Rowley24). A preliminary survey
identified 2 patients with translocation breakpoints localized within
the same intron of CBFA2(AML1), which is involved in the
majority of t(3;21) patients.25 We show here that these
balanced translocations involving CBFA2 occur predominantly in
therapy-related disorders and define a genomic region that appears to
be susceptible to exposure to cytotoxic drugs, especially those that
target DNA topoisomerase II.
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MATERIALS AND METHODS |
Patient material and cytogenetic analysis.
We examined samples from 30 patients (27 bone marrow and 3 peripheral
blood) with rearrangements of chromosome band 21q22, not including
t(3;21) or t(8;21). Most patients were identified at the University of
Chicago Hematology/Oncology Cytogenetics Laboratory between 1970 and
1996; 1 sample was contributed from the University Hospital
(Copenhagen, Denmark). Most samples were obtained at diagnosis of
leukemia (N = 25), 4 were obtained at the time of relapse, and 1 after
initiation of treatment. Diagnosis was based on morphologic and
cytochemical studies of peripheral blood smears and bone marrow
aspirate and biopsy specimens based on the FAB classification.
Twenty-four patients had myeloid disorders (AML de novo, primary MDS,
t-AML, and t-MDS) and 6 had ALL. Cytogenetic analysis with a
trypsin-Giemsa banding technique was performed on cells from bone
marrow and/or peripheral blood according to standard
procedures. Chromosomal abnormalities are described according to the
International System of Human Cytogenetic Nomenclature (1995).
FISH analysis.
The procedure used for FISH has been described.26 Probes
were labeled with biotin or digoxigenin and detected by fluorescein isothiocyanate (FITC)-conjugated avidin or rhodamine-conjugated antidigoxigenin antibodies. Metaphase chromosomes were identified by
4,6-diamidino-2-phenylindole dihydrochloride (DAPI) staining. Fluorescence images were captured using a cooled charge-coupled device
(CCD) camera (Photometrics, Tucson, AZ) and Nu200 software. Separate images of DAPI-stained cells and the fluorescence signal were merged using NIH Image 1.60 software (NIH, Bethesda,
MD).
Probes.
For CBFA2(AML1), the contiguous phage  walking clones (probe
13 and wc-1 through wc-10) and cosmid contigs that flank the CBFA2 breakpoint (AML21 centromeric and AML21 telomeric probes; Oncor, Inc, Gaithersburg, MD) have been described (Fig
1).4,6,27 A chromosome 21 painting probe (WCP 21q
SpectrumOrange; Vysis, Downers Grove, IL) was used for confirmation of
derivatives. For chromosome 17, two cosmids containing sequences from
RARA were used: COS34A, which is split by the t(15;17)
associated with acute promyelocytic leukemia, and PC7-611, which is
centromeric to the breakpoint (Richard S. Lemons, MD, University of
Utah, Salt Lake City, UT).27 The NF1
YAC was a gift from Douglas A. Marchuk, PhD (Duke University
Medical Center, Durham, NC). For chromosome 5, YAC A
(contains D5S112 sequences) and YAC C (contains D5S401) were used; both
are distal to the SMA locus in 5q13 (Lalitha Nagarajan, PhD, MD Anderson Cancer Center, Houston, TX).
| |
RESULTS |
Breakpoints on 21q22.
Seven patients were shown to have reciprocal translocations
involving CBFA2 when the cosmid contigs that flank the t(8;21) breakpoint were used. The locations of the breakpoints, clinical information, and complete karyotypes of these patients are listed in
Table 1. With trypsin-Giemsa banding, 2 patients had apparently identical translocations t(17;21) and either de
novo or t-AML (patients no. 1 and 4, Table 1;
Fig 2A and B). A cryptic translocation, t(1;21)(p36;q22), was detected in patient no. 7 (Fig 3F), who, by standard trypsin-Giemsa
banding, appeared to have an interstitial deletion, del(21)(q21q22.1)
(patient no. 70 reported in Pedersen-Bjergaard and
Philip12). In patient no. 6, with the t(14;21), both
derivative chromosomes were labeled with the telomeric cosmid contig
(Fig 3E). The der(21)t(14;21), but not the der(14), was labeled by probe 13, which was the most telomeric (5) walking clone
used in this study, indicating that this patient's breakpoint maps 5 of exon 5 of CBFA2 (Fig 1). The telomeric cosmid
contig is 5 to the t(8;21) breakpoint and 3 to the
t(12;21) breakpoint in 5 of 7 patients.27 Therefore, the
breakpoint in the t(14;21) is between that in most t(12;21) ALL
patients and the t(8;21) breakpoint region.
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| Fig 2.
Partial karyotypes from patients with rearrangements of
CBFA2. (A) Patient no. 1, t(17;21)(q11.2;q22); (B) patient no.
4, t(17;21)(q11.2;q22); (C) patient no. 2, t(5;21)(q13;q22); (D)
patient no. 3, t(12;21)(q24;q22); (E) patient no. 5, t(15;21)(q22;q22);
and (F) patient no. 6, t(14;21)(q22;q22). The abnormal homolog is on
the right in every example.
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| Fig 3.
Metaphase cells from patients with balanced reciprocal
translocations involving CBFA2. Signals (green) from
CBFA2 probes that were split by the translocation are indicated
on the der(21) (long arrow), the partner derivative (short arrow), and
the normal 21 (arrowhead) chromosomes in all examples, except as noted.
(A) Patient no. 1 with the t(17;21)(q11.2;q22) hybridized with the
biotinylated clone wc-6. (B) Patient no. 2, t(5;21) with walking clone
7. (C) Patient no. 3, t(12;21) with wc-8. (D) Patient no. 5, t(15;21)
with wc-5. (E) Patient no. 6, t(14;21) with AML21-telomeric cosmid
contig. (F) Patient no. 7, t(1;21)(p36;q22) with wc-5. (G) Patient no.
4, t(17;21) with AML21-centromeric contig. The der(21) (long arrow) and
normal 21 (arrowhead) were labeled. (H) Patient no. 4, t(17;21) with
AML21-telomeric contig. The der(17) (short arrow) and normal 21 (arrowhead) were labeled.
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Only 2 of the 30 patients had 21q22 breakpoints proximal to
CBFA2; 1 of these 2 had a t(10;21)(q22;q22) and the other had a
complex karyotype with a gain of a der(21)t(15;21). The other rearrangements of 21q22 were distal (telomeric) to CBFA2
(N = 14) or proved to be complex rearrangements (N = 3) or
unbalanced translocations leading to loss of chromosomal material (N = 4), rather than balanced reciprocal translocations.
Localization of breakpoints on partner chromosomes.
Two patients [patient no. 1, t(17;21), and patient no. 2, t(5;21)]
had sufficient material to investigate the location of the breakpoints
of the partner chromosomes. For patient no. 1, two cosmid probes
specific for the RARA locus localized to the der(21)t(17;21). A
YAC probe containing sequences for NF1 localized to the
der(17). Thus, the breakpoint on chromosome 17 is between the loci for
NF1 and RARA.
For patient no. 2, two YAC probes that are distal to the SMA
locus in 5q13 were shown to flank the breakpoint: YAC A, which includes
D5S112, was on the der(5) and YAC C, which includes D5S401, was on the
der(21). This spans a distance of about 10 Mb (L. Nagarajan, personal communication, July 1998).
Association with previous chemotherapy.
Of the 7 patients with balanced translocations involving CBFA2,
5 had a history of previous chemotherapy, whereas 2 did not. Four of
the 5 had presented with t-AML or t-MDS, and the fifth patient was
found to have a t(12;21)(q24;q22) after chemotherapy for AML evolving
from primary MDS. In contrast, of the 23 patients with 21q22
rearrangements but determined not to have translocations of
CBFA2, only 2 had t-AML/t-MDS. The karyotypes and FISH results for these 2 patients are listed in Table 2,
as are the treatment histories for all of the t-AML/t-MDS patients. The
association of a history of chemotherapy with CBFA2
translocations was significant by a Fisher's exact test (P < .003, N = 30).
The fifth patient with a translocation in CBFA2 and a history
of chemotherapy (patient no. 3) presented a diagnostic problem at the
time when the t(12;21)(q24;q22) was found. Initially, this 66-year-old
man had been diagnosed with primary MDS (refractory anemia with excess
blasts in transformation) progressing toward AML-M6 (Table 1). A normal
karyotype was noted, and interphase analysis of 500 cells from this
pretreatment sample did not indicate a CBFA2 translocation. The
patient received daunorubicin and cytarabine and achieved a complete
remission but relapsed after 11 months. He then had residual disease
for 18 months, at which time Auer rods were noted in a peripheral blood
sample. A bone marrow sample was analyzed, and the t(12;21) was noted
in 18 of 22 cells. Hence, the t(12;21) represents a change from the
pretreatment sample, but it is not clear whether it was associated with
a therapy-related myeloid leukemia or progression of the initial
disease.
| |
DISCUSSION |
We have shown that CBFA2 is involved in reciprocal
translocations between 21q22 and chromosome bands 17q11.2, 5q13, 1p36, 12q24, 15q22, and 14q22 in myeloid disorders (AML, MDS, t-AML, and
t-MDS). The breakpoints for 5 of the 7 CBFA2 translocations were localized to intron 6, the same intron that contains the breakpoint in most patients with the t(3;21).6 This is one intron downstream from the location of most of the breakpoints in the
t(8;21).28 By analogy with the t(8;21) and t(3;21), the fusion transcript should include the 5 region through exon 6. It
will be of interest to compare motifs of these partner genes with those
of ETO and EAP, MDS, and EVI1 to see
whether they share similar characteristics.
Thus, at present, we know of 9 translocation partners for
CBFA2. Six are described here; 1 of these was found to be a
potential recurring abnormality [the t(17;21)]. In 8 translocations,
including the t(8;21) and t(3;21), CBFA2 provides the 5
part of the fusion gene and the leukemias are myeloid, whereas in the
t(12;21)(p13;q22), CBFA2 is 3 and the phenotype is ALL.
The finding of 2 AML patients (1 with AML-M2 [patient no. 1] and 1 t-AML [patient no. 4]) with identical cytogenetic breakpoints t(17;21)(q11.2;q22) suggests a rare recurring abnormality, despite the
different diagnoses. It is well established that recurring translocations involving 11q23 occur after treatment with topoisomerase II inhibitors,10,11,29,30 and MLL was demonstrated
to be affected in such cases.31 Thus, by analogy to
MLL, it is not surprising to find that CBFA2 is
translocated in both de novo and therapy-related myeloid disorders with
a balanced translocation of 21q22, even when the partner chromosome is
the same. In fact, the t(3;21) that involves CBFA2 and is usually
associated with prior therapy has also been observed in at least one de
novo case.9
The latency period from the initial treatment for the primary neoplasia
to development of t-AML/t-MDS in these 4 patients had a mean of 59 months (range, 52 to 63 months). The interval from initial exposure to
topoisomerase II inhibitors to development of t-AML/t-MDS was, on
average, 53 months (range, 36 to 63 months), which is longer than for
most MLL translocations. In one such study, the time from
initial treatment to t-AML/t-MDS was an average of 23 months (range, 9 to 35 months; N = 9); for the time from first topoisomerase II
exposure, the average was 20 months (range, 9 to 35 months).31 Furthermore, t-MDS was present before t-AML in 2 patients reported here (patients no. 5 and 6), whereas
MLL-rearranged t-AML typically presents abruptly, without a
preleukemic phase.
The association of CBFA2 rearrangements with prior therapy
supports the conclusions of Stanulla et al,32 who found
site-specific CBFA2(AML1) cleavage inducible in vivo by
topoisomerase II inhibitors for several cell types. In their study,
CBFA2 sites were less specific (in that fainter bands
suggestive of additional cleavage sites were found) and less sensitive
(in that fewer cell lines and fewer cells had significant breakage at
the main cleavage site) than in MLL. The major site-specific
cleavage site in CBFA2 mapped to intron 5, slightly 5 of
the breaks for most of the patients reported here. In this study, we
found 2 of 4 therapy-related breakpoints in intron 6, 1 was 5 of
exon 5 and only 1 breakpoint was in intron 5 (Fig 1 and Table 1).
Unfortunately, there was no material available to determine the precise
location of this patient's breakpoint. However, the 2 breakpoints in
intron 6 are located in wc-5, within 10 to 20 kb of the in vivo
cleavage site (Fig 1). This same walking clone contained the breakpoint
of a t(3;21) from a CML blast crisis patient.6 It will be
important to examine this region for the presence of a topoisomerase II consensus cleavage site. However, characterizaton of the functions of
the various CBFA2 fusion proteins will be critical to
understanding the process of transformation in de novo and
therapy-related leukemia.
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NOTE ADDED IN PROOF |
Another CBFA2 translocation has been described, the
t(16;21)(q24;q22), a rare translocation found in patients with MDS
(N=1) or t-MDS/t-AML (N=3). The CBFA2 breakpoint occurs
between exons 5 and 6. As in the t(8;21) and t(3;21), CBFA2
contributes 5 sequences to a fusion gene. The partner gene,
MTG16, is highly homologous to
MTG8(ETO).33
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FOOTNOTES |
Submitted April 2, 1998;
accepted June 8, 1998.
Supported in part by National Institutes of Health Grants No. CA40046
(J.D.R., R.A.L., and M.M.L.) and CA42557 (J.D.R.) and by the G. Harold
and Leila Y. Mathers Foundation (J.D.R.). G.N. is a Scholar of the
Leukemia Society of America.
Address reprint requests to Diane Roulston, PhD, Section of
Hematology/Oncology, The University of Chicago Pritzker School of
Medicine, 5841 S Maryland Ave (MC2115), Chicago, IL 60637.
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 |
For expert technical assistance, we thank the staff of the Gene Mapping
Laboratory. For the contribution of patient material used in the
survey, we thank Jens Pedersen-Bjergaard, MD, PhD, Avery Sandberg, MD,
DSc, Rod Morgan, MS, and Andrew Carroll, PhD. We thank the following
physicians for providing patient treatment histories: John E. Godwin,
MD, Patrick J. Stiff, MD, Jim Cohn, MD, and Michael J. Thirman, MD.
| |
REFERENCES |
1.
Swirsky DM,
Li YS,
Matthews JG,
Flemans RJ,
Rees JKH,
Hayhoe FGJ:
8;21 translocation in acute granulocytic leukaemia: Cytological, cytochemical and clinical features.
Br J Haematol
56:188,
1984
2.
Nucifora G,
Dickstein JI,
Torbenson V,
Roulston D,
Rowley JD,
Vardiman JW:
Correlation between cell morphology and expression of the AML1/ETO chimeric transcript in patients with acute myeloid leukemia without the t(8;21).
Leukemia
8:1533,
1994[Medline]
[Order article via Infotrieve]
3.
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
88:10431,
1991[Abstract/Free Full Text]
4.
Erickson P,
Gao J,
Chang K-S,
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
80:1825,
1992[Abstract/Free Full Text]
5.
Nucifora G,
Rowley JD:
AML1 and the 8;21 and 3;21 translocations in acute and chronic myeloid leukemia.
Blood
86:1,
1995[Free Full Text]
6.
Nucifora G,
Birn DJ,
Espinosa R,
Erickson P,
Gao J,
Le Beau MM,
Roulston D,
Drabkin H,
Rowley JD:
Involvement of the AML1 gene in the t(3;21) in therapy-related leukemia and in chronic myeloid leukemia in blast crisis.
Blood
81:2728,
1993[Abstract/Free Full Text]
7.
Rubin CM,
Larson RA,
Anastasi J,
Winter JN,
Thangavelu M,
Vardiman JW,
Rowley JD,
Le Beau MM:
t(3;21)(q26;q22): A recurring chromosome abnormality in therapy-related myelodysplastic syndrome and acute myeloid leukemia.
Blood
76:2594,
1990[Abstract/Free Full Text]
8.
Rubin CM,
Larson RA,
Bitter MA,
Carrino JJ,
Le Beau MM,
Diaz MO,
Rowley JD:
Association of a chromosomal 3;21 translocation with the blast phase of chronic myelogenous leukemia.
Blood
70:1338,
1987[Abstract/Free Full Text]
9.
Johansson B,
Fioretos T,
Garwicz S,
Heim S,
Mitelman F:
t(3;21)(q26;q22) with AML1 rearrangement in a de novo childhood acute monoblastic leukemia.
Br J Haematol
92:429,
1996[Medline]
[Order article via Infotrieve]
10.
Pedersen-Bjergaard J,
Philip P:
Balanced translocations involving chromosome bands 11q23 and 21q22 are highly characteristic of myelodysplasia and leukemia following therapy with cytostatic agents targeting at DNA-topoisomerase II.
Blood
78:1147,
1991[Free Full Text]
11.
Larson RA,
Le Beau MM,
Ratain MJ,
Rowley JD:
Balanced translocations involving chromosome bands 11q23 and 21q22 in therapy-related leukemia.
Blood
79:1892,
1992[Free Full Text]
12.
Pedersen-Bjergaard J,
Philip P:
Cytogenetic characteristics of therapy-related acute nonlymphocytic leukaemia, preleukaemia and acute myeloproliferative syndrome: Correlation with clinical data for 61 consecutive cases.
Br J Haematol
66:199,
1987[Medline]
[Order article via Infotrieve]
13.
Nucifora G,
Begy CR,
Kobayashi H,
Roulston D,
Claxton D,
Pedersen-Bjergaard J,
Parganas E,
Ihle J,
Rowley JD:
Consistent intergenic splicing and production of multiple transcripts between AML1 at 21q22 and three unrelated genes at 3q26 in (3;21)(q26;q22) translocations.
Proc Natl Acad Sci
91:4004,
1994[Abstract/Free Full Text]
14.
Romana SP,
Le Coniat M,
Berger R:
t(12;21): A new recurrent translocation in acute lymphoblastic leukemia.
Genes Chromosom Cancer
9:186,
1994[Medline]
[Order article via Infotrieve]
15.
Romana SP,
Mauchauffe M,
Le Coniat M,
Chumakov I,
Le Paslier D,
Berger R,
Bernard OA:
The t(12;21) of acute lymphoblastic leukemia results in a tel-AML1 gene fusion.
Blood
85:3662,
1995[Abstract/Free Full Text]
16.
Golub TR,
Barker GF,
Bohlander SK,
Hiebert SW,
Ward DC,
Bray-Ward P,
Raimondi SC,
Rowley JD,
Gilliland DG:
Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia.
Proc Natl Acad Sci USA
92:4917,
1995[Abstract/Free Full Text]
17.
Romana SP,
Poirel H,
Leconiat M,
Flexor M-A,
Mauchauffe M,
Jonveaux P,
Macintyre EA,
Berger R,
Bernard OA:
High frequency of t(12;21) in childhood B-lineage acute lymphoblastic leukemia.
Blood
86:4263,
1995[Abstract/Free Full Text]
18.
Shurtleff SA,
Buijis A,
Behm FG,
Rubnitz JE,
Raimondi SC,
Hancock ML,
Chan GC-F,
Pui C-H,
Grosveld G,
Downing JR:
TEL/AML1 fusion resulting from a cryptic t(12;21) is the most common genetic lesion in pediatric ALL and defines a subgroup of patients with an excellent prognosis.
Leukemia
9:1985,
1995[Medline]
[Order article via Infotrieve]
19.
McLean TW,
Ringold S,
Neuberg D,
Stegmaier K,
Tantravahi R,
Ritz J,
Koeffler HP,
Takeuchi S,
Janssen JWG,
Seriu T,
Bartram CR,
Sallan SE,
Gilliland DG,
Golub TR:
TEL/AML1 dimerizes and is associated with a favorable outcome in childhood acute lymphoblastic leukemia.
Blood
88:4252,
1996[Abstract/Free Full Text]
20.
Liu P,
Tarle SA,
Hajra A,
Claxton DF,
Marlton P,
Freedman M,
Siciliano MJ,
Collins FS:
Fusion between transcription factor CBF beta/PEBP2 beta and a myosin heavy chain gene in acute myeloid leukemia.
Science
261:1041,
1993[Abstract/Free Full Text]
21.
Ghozi MC,
Bernstein Y,
Negreanu V,
Levanon D,
Groner Y:
Expression of the human acute myeloid leukemia gene AML1 is regulated by two promoter regions.
Proc Natl Acad Sci USA
93:1935,
1996[Abstract/Free Full Text]
22.
Okuda T,
van Deursen J,
Hiebert SW,
Grosveld G,
Downing JR:
AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis.
Cell
84:321,
1996[Medline]
[Order article via Infotrieve]
23.
Wang Q,
Stacy T,
Binder M,
Marin-Padilla M,
Sharpe AH,
Speck NA:
Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis.
Proc Natl Acad Sci USA
93:3444,
1996[Abstract/Free Full Text]
24.
Rowley JD:
Rearrangements involving chromosome band 11q23 in acute leukemia.
Semin Cancer Biol
4:377,
1993[Medline]
[Order article via Infotrieve]
25.
Roulston D,
Nucifora G,
Dietz-Band J,
Le Beau MM,
Rowley JD:
Detection of rare 21q22 translocation breakpoints within the AML1 gene by fluorescence in situ hybridization.
Blood
82:532a,
1993(abstr, suppl 1)
26.
Rowley JD,
Diaz MO,
Espinosa R,
Patel YD,
van Melle E,
Ziemin S,
Taillon-Miller P,
Lichter P,
Evans GA,
Kersey JD,
Ward DC,
Domer PH,
Le Beau MM:
Mapping chromosome band 11q23 in human acute leukemia with biotinylated probes: Identification of 11q23 translocation breakpoints with a yeast artificial chromosome.
Proc Natl Acad Sci USA
87:9358,
1990[Abstract/Free Full Text]
27.
Fears S,
Vignon C,
Bohlander SK,
Smith S,
Rowley JD,
Nucifora G:
Correlation between the ETV6/CBFA2 (TEL/AML1) fusion gene and karyotypic abnormalities in children with B-cell precursor acute lymphoblastic leukemia.
Genes Chromosom Cancer
17:127,
1996[Medline]
[Order article via Infotrieve]
28.
Miyoshi H,
Kozu T,
Ohira M,
Shimizu K,
Mitani K,
Hirai H,
Imai T,
Yokoyama K,
Soeda E,
Ohki M:
Alternative splicing and genomic structure of the AML1 gene involved in acute myeloid leukemia.
Nucleic Acids Res
23:2762,
1995[Abstract/Free Full Text]
29.
Pedersen-Bjergaard J,
Rowley JD:
The balanced and the unbalanced chromosome aberrations of acute myeloid leukemia may develop in different ways and may contribute differently to malignant transformation.
Blood
83:2780,
1994[Abstract/Free Full Text]
30.
Roulston D,
Anastasi J,
Rudinsky R,
Nucifora G,
Zeleznik-Le N,
Rowley JD,
McGavran L,
Tsuchida M,
Hayashi Y:
Therapy-related acute leukemia associated with t(11q23) following a primary acute myeloid leukemia with t(8;21): A study of two cases.
Blood
86:3613,
1995[Free Full Text]
31.
Gill Super HJ,
McCabe NR,
Thirman MJ,
Larson RA,
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]
32.
Stanulla M,
Wang J,
Chervinsky DS,
Aplan PD:
Topoisomerase II inhibitors induce DNA double-strand breaks at a specific site within the AML1 locus.
Leukemia
11:490,
1997[Medline]
[Order article via Infotrieve]
33.
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 in a novel member of the MTG8(ETO) family.
Blood
91:4028,
1998[Abstract/Free Full Text]
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|
|
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Abstract
Introduction
Abstract