Download Cloning of the ALL.1 Fusion Partner, the AF

[CANCER RESEARCH 53, 5624-5628, December 1, 1993 I
Advances in Brief
Cloning of the ALL.1 Fusion Partner, the AF-6 Gene, Involved in Acute Myeloid
Leukemias with the t(6;ll) Chromosome Transiocation 1
17, P r a s a d , Y. Gu, H. Alder, T. N a k a m u r a , O. C a n a a n i , H. Saito, K. H u e b n e r , R. P. Gale, P. C. NoweU, K. K u r i y a m a ,
Y. M i y a z a k i , C. M . Croce, a n d E. C a n a a n i 2
Jefferson Cancer Institute, Jefferson Cancer Center and Department of Microbiology and Immunology, Jefferson Medical College of Thomas Jefferson University, Philadelphia~
Pennsylvania 19107lR. R, Y G., H. A., T. N., O. C., H. S., K. H., C. M. C., E. C.]; University of California Medical Center, Los Angeles, California 90024 [R. P. G.]; Un&ersity
of Pennsyh,ania, Philadelphia, Pennsylvania 19104 [P. C. N.]; and Nagasaki University School of Medicine, Nagasaki 852, Japan [K. K., Y M.]
Abstract
Reciprocal chromosome translocations involving 11q23 are frequently
associated with acute leukemias, with the t(4;ll) translocation predominating among acute lymphoblastic leukemias, and the t(9;ll), t(ll;19) and
t(6;ll) translocations most common among acute myeloid leukemias. In
each of these translocations the ALL-1 gene, located at 11q23 and constituting the human homologue of Drosophila trithorax, fuses to a specific
gene on the partner chromosome to produce a chimeric protein. Here we
report the cloning and the characterization of the partner gene from
chromosome 6 (AF.6). AF-6 is expressed in a variety of cell types and
encodes a protein of 1612 amino acids. The protein contains short stretches
rich in prolines, charged amino acids, serines, or glutamines. In addition,
the AF-6 protein contains the GLGF motif shared with several proteins of
vertebrates and invertebrates thought to be involved in signal transduc.
tion at special cell-cell junctions.
ferase; the reciprocal protein product will include most or all of the
zinc fingers. Cytogenetic analysis of complex 11q23 translocations
indicated that the chromosome der(ll), but not the reciprocal derivative, is the common feature of these abnormalities (13). This suggested that the fusion protein product containing the NH2 terminus of
ALL-1 is the oncogene.
The partner genes in the t(4;ll), t(9;ll), and t(ll;19) were cloned
and characterized by us or others (7, 8, 12, 14, 15) and were designated AF-4, AF-9, and E N L , respectively. AF-9 and E N L encode
highly homologous proteins that vary completely from the polypeptide coded by the A F - 4 gene. The three proteins, however, share a
nuclear targeting sequence and serine/proline-rich domains (14). In
the present communication we describe the cloning and characterization of the partner gene involved in a fourth common translocation
involving l lq23, the t(6; ll)(q27;q23).
Introduction
The majority of infant acute leukemias and at least 5% of ALLs 3
and AMLs of older children and adults show abnormalities of chromosome band 11q23 (1, 2). In addition, 11q23 aberrations occur at
very high frequency in secondary acute leukemias induced by treatment of malignancies with inhibitors of topoisomerase II (3, 4). Leukemias involving 11q23 abnormalities share unique clinical and biological features such as massive cell burden, frequent mixed lineage
with markers of both lymphoid and myeloid blasts, and a bad prognosis.
Recently we cloned (5) a DNA segment from chromosome 11
which is rearranged in most or all 11q23 abnormalities (6). We and
others have subsequently cloned the gene spanning the breakpoint
cluster region (7, 8). This gene was designated ALL-1 (5-7), M L L (9),
or HRX (8, 10). A L L - 1 shows strong homology to three regions with
Drosophila trithorax and therefore is thought to constitute the human
homologue of the latter. ALL-l-encoded protein has two types of
DNA binding motifs, zinc fingers and AT hooks; in addition it contains
a domain shared with DNA methyltransferase and is presumably
involved in recognition of hemimethylated and unmethylated DNA
(11, 12).
11q23 chromosome translocations sever theALL-1 gene in a region
containing exons 5-11 and result in fusion of the open reading frames
of ALL-1 and the partner genes in phase. One protein fusion product
will contain the NH2-terminal --1400 amino acids of A L L - 1 including
the AT hook motifs and the domain shared with DNA methyltransReceived 10/4/93; accepted 10/28/93.
The costs of publicationof this article were defrayedin part by the paymentof page
charges. This article must thereforebe herebymarkedadvertisement in accordancewith
18 U.S.C. Section 1734 solely to indicatethis fact.
Supportedby grantsfromthe NationalCancerInstitute(CA39860)and from the Falk
Medical ResearchTrust; Genbankaccessionnumberis U02478.
z To whom requests for reprints should be addressed.
3 The abbreviationsused are: ALL, acute lymphoblasticleukemia;AML, acute myeloid leukemia;cDNA, complementaryDNA; RT-PCR, reversetranscription-polymerase
chain reaction.
Materials and Methods
Patients and Cells. The patient 01 was a 47-year-old female, diagnosed as
AML(M4). Her karyotype was 46,XX, t(6;ll)(q27;q23) in 20 of 20 of bone
marrow ceils analyzed. Patient Ed was a male diagnosed as AML(M5) with a
karyotype of 46,XY,del(llq23). The celI lines used for RNA analysis included
K562 and KC122 (erythroid and myeloid acute phase of chronic myeloid
~eukemia) (16, 17), B-t and MV4:ll [ALL with the t(4;11) abnormality (18,
19)], SKDHL (B-cell lymphoma) (20), T98G (glioblastoma) (21), and the 293
cell line derived from kidney (22).
Molecular Cloning. The rearranged genomic fragments of ALL-1 from
patients 01 and Ed were cloned into the EMBL-3 phage vector (Promega) after
partial digestion of the DNAs with the MboI enzyme and size selection. Phage
libraries were screened using a 0.86-kilobase BamHI fragment derived from
ALL-I cDNA and spanning exons 5-11. A normal genomic library was constructed in a similar way from normal WBC DNA. The cDNA library was
constructed utilizing a kit from Pharmacia. Cytoplasmic polyadenylate-selected RNA was prepared from KC122 cells. For RT-PCR reactions, aliquots of
2 ~g of patients' RNAs were reverse transcribed utilizing the AF-6 oligonucleotide 5' ATC TGAAT-F CTC CGC TGA CAT GCA CTI" CAT AG 3'. The
cDNA was amplified using the same AF-6 primer together with the ALL.1
primer 5' ATC TGA ATI" CTC CGC TGA CAT GCA c T r CAT AG 3'. (Both
primers contained cloning sites at their 5' termini.) The amplified products
were cloned into the SK plasmid vector and sequenced.
Sequencing. cDNAs and genomic DNAs were excised from the phage
vectors and recloned into the SK plasmid vector. Sequencing was performed
using the ABI automatic sequencer. The sequence was analyzed using the
FASTA, TFASTA, and motifs programs.
Results
A rearranged ALL-1 segment was cloned from the genomic DNA of
leukemic cells of patient 01. Mapping of this segment indicated that
it originated from the der(6) chromosome (Fig. 1A). Sequencing of the
junction region (Fig. 1C) showed neither extra nucleotides nor heptamer-like signal at the junction point. Therefore, unlike two t(4;ll)
and one (9;11) translocation breakpoints that we previously studied
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CLONING OF AF-6 GENE
,++
A
2kb
Tel
Cen
B
R
G
X
Lql
5
R
H
XXBH
f f
6
H X
R
7
R
8
Chr.llq23
--
12kb
91011
G
X
II III I
R
I I
XXBH
IIII
der (6)
RVP0.5
R
H
H X
RXR
H
X
HB X
HX
+el
HR B
a
Chr.
XR0.5
b
6q27
Xinf0.6
C
~T~TGTTTCTCTGCCATTTU~AC~TGTATTCTATTTTGT~TTATCcTTGAcTTCTATGTAGA~G~TTTCTTAAAATTAAGAAA
IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIiiiiiiiiiiiiiiiiiiiiiiiiii
TTCC TCATAGGAAATAAAATCTITTAAATTAGCTTGTTTAG
CTTATCC~TTCTATGTAGATGGCAGTGGAATTTCTTAAAATTAAGAAA
Chr. i lq2 3
der (6)
lllllllllllllllllllllllllllllllllllllllillllllllillll
TTC~TCA~ACK~'AAA~AAAATCTTTTAAATT~~L-~-A-~C~AAAACCCAACAAAACCATTG~A~TTTTAGTTAC~~~A~~
Chr. 6q2 7
Fig. 1. Oenomic analysis of the t(6;ll)(q27;q23) chromosome translocation. (A) Physical map of the t(6;ll) junction in patient 01, as well as of the corresponding regions from
chromosomes 11 and 6. The RVP0.5 probe was used to isolate the corresponding normal DNA of 6q27. (B) Chromosome 6+specific probe XR0.5 detects DNA rearrangement in the
bone marrow ceils from the patient (Ed), whose karyotype showed 11q23 deletion; high moleculer weight DNAs were digested with BamHI. (C) Sequence of the t(6;ll) breakpoint
region in patient 01. Cen and Tel denote the direction of the centromeres and telomeres of the two chromosomes. Open vertical boxes rcpresent defined exons. Restriction sites: B,
BamHI; 11, HindlII; G, BgllI; R, EcoRI; X, Xba]. kb, kilobase.
(23, 24), here the VDJ recombinase was probably not involved in the directly demonstrate a fused transcript we performed RT-PCR reactions on RNAs from patients 01 and Ed using ALL-1 and AF-6 primers
recombination process.
We next used a repeat-free EcoRV-PstI 0.5-kilobase fragment (RVP flanking the expected junction region. Products of the reactions were
0.5) as a probe to clone the corresponding region from normal DNA cloned, screened for hybridization to ALL-1 and AF-6 probes, and
(Fig. IA, bottom). To examine whether this region of chromosome 6 sequenced. The RT-PCR products of both patients showed identical
constitutes a breakpoint cluster region, we probed genomic blots of chimeric ALL-1/AF-6 RNAs transcribed from the der(ll) chromosome (Fig. 2C). The two open reading frames were linked in phase.
some selected patients' DNAs with the 0.5-kilobase XbaI-EcoRI
The nucleotide and the amino acid sequences of AF-6 were exam(XRO.5) radiolabeled fragment. While the DNA of another patient
with AML and t(6;ll) showed only germ line configuration of this ined for motifs and homology to other genes. Throughout the protein,
region, the DNA of the patient Ed with AML and the del(llq23) but in particular towards the COOH terminus of AF-6 there exist small
aberration contained a rearranged BamHl fragment of 12 kilobases domains rich in prolines, serines, acidic amino acids, or glutamines.
(Fig. 1B). This indicated that the cloned DNA spanned a breakpoint AF-6 protein within residues 745-925 shows 23.2% identity over 181
cluster region and that a cytogenetic pattern of del(llq23) could amino acids with the COOH terminus of yeast myosin-1 isoform (25).
The protein also shows high similarity, although low identity, (66%
correspond to a t(6;11) translocation.
The entire area of 30 kilobases cloned from 6q27 was searched for similarity plus identity) over amino acids 1000-1594 to amino acids
1400-1980 of the myosin heavy chain from Dictyostelium discoideum
segments reacting with clones from a normal cDNA library. A 0.6kilobase HinfI DNA reacted with the K12 cDNA clone (Fig. 14). By (26). In the latter protein this region is part of the tail domain which
subsequent "walking" it was possible to clone overlapping cDNA assumes, due to a high a-helical potential, a rod structuce. A striking
clones which spanned the complete coding region of the gene. We homology was detected in the polypeptide spanning amino acids
named the latter AF-6 for ALL-1 fused gene from chromosome 6. 997-1080. A series of amino acids in this domain are conserved (Fig.
AF-6 encodes a protein of 1612 amino acids. In cDNA clone K10 we 3) in three other proteins: in the human tight junction protein ZO-1
find two additional amino acids, glutamic acid at position 101 and a (27); in the rat PSD-95 protein present in brain synapses (28); and in
lysine in position 139; both are probably due to alterations in splicing a tumor suppressor gene of Drosophila (dig) located at septate juncsimilar to those which we previously detected in ALL-1 (11, 14). To tions (which are thought to be the invertebrate equivalent of tight
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CLONING OF AF-6 GENE
I Kb
KIO
K12
9
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K28
....
A
AF-6 cDNA
S
i
H
H
A
B
l ill
I
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H$
III
ATG
K26
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A
i {
TAG
B
1
MSAGGRDEERRKLADI I HHWNANRLDLFE ISQPTEDLEFHGVMRFYFQDKAAGNFATKCI RVSS TATTQDVIETLAEKFRP DMRMLSSP KYSLYEVHVSG
i01
ERRLD ID EKP LVVQLNWNKDDREGRFVLKNENDAI PPKAQSNGP EKQEKEGVI QNFKRTLSKKE KKEKKKREKEALRQASDKDDRPFQGEDVENS RLAAE
201
VYKDMPETSFTRT ISNPEVVMKRRRQQKLEKRMQEFRSSDGRPDSGGTLRIYADSLKPNI PYKT I LLSTTDPADFAVAEALEKYGLEKENPKDYC IARVM
301
LPPGAQHSDEKGAKE I I LDDDECP LQIFREWP SDKG ILVFQLKRRP PDHIPKKTKKHLEGKTPKGKERADGSVYGSTLP PEKLPYLVELSPDGSDSRDKP
401
KLYRLQLSVTEVGTEKLDDNSI QLFGPG IQPHHCDLTNMDGVVTVTPRSMDAETYVEGQR ISETTMLQSGMKVQFGASHVFKFVDPSQDHAIAKRSVDGG
501
LMVKGPRHKPG IVQETTFDLGGDI HSGTALPTSKSTTRLDSDRVSSASSTAERGMVKPMI RVEQQp DYRRQESRTQDASGP EL ILPASI EFRESSEDSFL
601
SAI INYTNSSTVHFKLSPTYVLYMACRYVLSNQYRPDI SP TERTH_KVIAVVNKMVS~9~EGVI QKQKNIAGALAYWMANASE LLNF IKQDRDLSRI TLDAQ
701
DVLAHLVQMAFKYLVHCLQSELNNYMPAFLDDPEENSLQRPK IDDVLHTLTGAMSLLRRCRVNAALT IQLFSQLFHF INMWLFNRLVTDPDSGLCSHYWG
801
AI I RQQLGHIEAWAEKQGLE LAADCHLSRIVQATTLLTMDKYAP DD IPNINSTCFKLNSLQLQALLQNYHCAP DEPF Ip TDLI ENVVTVAENTADELARS
901
DGREVQLEEDPDLQLPFLLPEDGYSCDVVRNIPNGLQEFLDP LCQRGFCRLIPHTRSPGTWTIYFEGADYESHLLRENTELAQPLRKEPEI
ITVTLKKQN
I001
GMGLS IVAAKGAGQDKLG IYVKSVVKGGAADVDGRLAAGDQL LSVDGRSLVG LSQE RAAE LMTRTS SVVT LEVAKQGAI YHGLAT LLNQP SPMMQRI SDR
1101
RG•GKPRPKsEGFELYNNSTQNG•PESPQLPWAEYSEPKKLPGDDRLMKNRADHR•SPNVANQPP•PGGKSAYASGTTAKIT•VsTGNLCTEEQTPPPRP
1201
EAYPI PTQTYTREYFTFPASKSQDRMAPPQNQWPNYEEKPHMHTDSNHSS IAI QRVTRSQEELREDKAYQLERHRIEAA
1301
SSQEHLNHSSKSVTPASTLTKSGPGRWKTPAAI PATPVAVSQP IRTDLPP pp pp PPVHYAGDFDGMSMDLP Lppp PSANQI GLPSAQVAAAERRKREEHQ
1401
RWYEKEKAP LEEERERKRREQERKLGQMRTQSLNPAPFSP LTAQQMKPEKPSTLQRPQETVI RE LQpQQQPRTIERRDLQY ITVSKEELSSGDSLSPDPW
1501
KRDAKEKLEKQQQMHIVDMLsKEIQELQ•KPDRSAEEsDRLRKLMLEWQFQKRLQE•KQKDEDDEEEEDDDVDTMLIMQRLEAERRARVKGGVLWLCP•V
1601
VPILASACFPWG*
RKSDSDMWINQSSSLDSS T
1612
C
GTCCAGAGCAGAGCAAACAGAAAAAAGT GGC TCCCCGCCCAAG TATCCC TG TAAAACAAA
P E Q S K Q K K V A P R P S I P V K Q K
ALL-1 exon6 ~ _
AF-6 exon
AAC CAAAAGAAAAGGATT TGGAGTTCCATGGAGTGAT GAGATT TTAT TT TCAAGATAAAG
P K E K D L E F H G V M R F Y F Q D K A
C TGCTGGAAACT TTGCAACAAAATGTAT TCGGGTC TC TAGT AC TGCCACCACTCAAGAT G
A G N F A T K C I R V S S T A T T Q D V
TAATCGAAACC-C T C G C G G ~ F ~ T TTCGACCTGATATGCGAATGC TGTCCTCTCCCAAGT
I E T L A E K F R P D M R M L S S P K Y
AT TCAC TCTATGAAGTGCATGTCAGCGGAG
S L Y E V H V S G
Fig. 2. Cloning and sequencing of AF-6 eDNA and of ALL-1/AF-6 fusion transcript. (,4)AF-6 cDNA clones. - - - - , different sequences possibly representing alternative non-coding
exons. Restriction sites: ,4, Apal; B, BamHI; tt, H/ndlII; S, SacI. (B) Predicted amino acid sequence o l A F - 6 cDNA coding region. Arrow, RNA fusion point. (C) Fusion transcript of
ALL-1 and AF-6 cloned from the RNAs of patients 01 and Ed. Kb, kilobase.
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CLONING OF AF-6 GENE
AF- 6
ZO-I (3)
psd95 (2)
dlg (3)
KKQNGMGL S IVAAKGAGQ.. DKLGXYVKSWKGGAADVDGRIdkAGDQLLSVDGRSLVGLS Q~t~AE LM.. TRTS SV%'TLEVAKQGAIY
RKGD SVGLRL ..... AGG.. NDVGXF%rAGVLED SPAAKEG. LEEGDQ ILRVNNVDF TN I IRZEAVLFLLDLPKGEEVTI LAQKKKDVY
KGPKGL~SIAGGVGNQHIPGDNSXYVTKIIEGGA~KDGR~IGDKIZdkVNSVGLEDVMHI~AVAAL..
KNTYDVVYLKVAKPSNAY
KGPQGL&'FNIVG .... GE. .DGQGIrY%'SFI LAGGPJ~3LGSEId~(~DQLLS~qNVNLTHATHZEAAQAL.. KTSGGVVTLLAQYRPEEM
Fig. 3. Comparison of the GLGF repeat within the AF-6 protein to GLGF repeats of other proleins. GLGF repeats are the third GLGF in human ZO-1 (ZO-1 3), the second GLGF
in rat PSD95 (PSD95 2), and the third GLGF in Drosophila large disc tumor suppressor gene (dtg3). Bold amino acids are consensus amino acids conserved among the four proteins.
D. discoideum; this domain presumably confers the rod structure on
the myosin protein. Within this region AF-6 displays a remarkable
homology to the GLGF repeat found in the ZO-1, PSD-95, and dig
proteins from human, rat, and Drosophila, respectively. The first and
the third proteins are thought to play a role in signal transduction on
the cytoplasmic surface of intercellular junctions (27, 29). The second
protein localizes to synaptic junctions and is thought to be involved in
synaptic signaling or organization (28). The three proteins are associated with the cytoskeleton. Therefore, the presence of the GLGF
domain in AF-6 raises the possibility that AF-6 is not a nuclear
protein.
junctions) (29). In this domain, termed the GLGF repeat (28), AF-6
shows identity of 28, 36, and 42% and similarity of 57, 59, and 67%
t6 the human, rat, and Drosophila proteins, respectively.
To examine the expression of AF-6 in different cell types, we
performed a Northern analysis on RNAs extracted from several cell
lines (Fig. 4). An 8-kilobase transcript was detected in cell lines of
myeloid (Fig. 4, Lane a), erythroid (Fig. 4, Lane b), lymphoid (Fig. 4,
Lanes c-e), glial (Fig. 4, Lane f) and epithelial (Fig. 4, Lane g) origin.
Thus, it appears that AF-6 is expressed in a variety of hematopoietic
and nonhematopoietic cells.
Discussion
Acknowledgments
The t(6;11)(q27;q23) translocation is one of the most frequent
translocations involving 11q23. Cloning of the AF-6 gene involved in
this abnormality should enable now the use of Southern blotting and
the RT-PCR technique to identify relevant patients whose karyotype
was different, complex, or not clear. In addition it is possible now to
examine residual disease in patients in remission. The analysis reported here of the patient Ed illustrates the first point. This patient
showed a typical del(llq23) abnormality. Using the molecular approaches we found here that he had the ALL-1/AF-6 fusion product.
Presumably, del(llq23) and t(6;ll) are difficult to distinguish cytogenetically. Using chromosome 6-specific probes and fluorescence in
situ hybridization analysis, others have recently concluded that some
patients with del(llq23) in fact carry the t(6;ll) chromosome translocation (30).
One of the main reasons for cloning AF-6 was to see if it is related
to the partner genes AF-4, AF-9, and ENL. Among these, AF-9 and
ENL are highly reiated. However, AF-6 showed no sequence homology to any of the three partner genes. Short domains rich in prolines,
serines, and charged amino acids were the only motifs shared by the
four genes. The COOH terminus of AF-6 showed homology to the tail
domain of myosin-1 isoform from yeast and myosin heavy chain from
We thank Jean Letofsky, Christine Beatty, and Kate Wildauer for their
technical assistance.
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5 kb-
2 kb-
a
b
c
d
e
f
g
Fig. 4. Northern analysis of AF-6 RNA in human cell lines. From 5 to 10 /zg of
polyadenylated RNA were analyzed on agarose gel containing formaldehyde. RNAs were
obtained from lines KCL22, K562, B-l, MV4;ll, SKDHL, T98G, and 293 (Lanes a-g,
respectively).
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CLONING OF AF-6 GENE
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Research.
Cloning of the ALL-1 Fusion Partner, the AF-6 Gene, Involved
in Acute Myeloid Leukemias with the t(6;11) Chromosome
Translocation
R. Prasad, Y. Gu, H. Alder, et al.
Cancer Res 1993;53:5624-5628.
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