1. Art and Diseño

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Unusual Deletions Within the Immunoglobulin Heavy-Chain
Locus in Acute Leukemias
By M.J.S. Dyer, J.M. Heward, V.J. Zani, V. Buccheri, and D. Catovsky
We have investigated the structure of the l g heavy (IGH)
chain locus in 309 cases of acute leukemia. Seventy-one
cases of B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) were analyzed: in six cases deletion of joining
(JH)segments in the presence of cytogenetically normal
chromosome 14 was observed. Similar deletions were
seen in 1 out of 8 cases of biphenotypic acute leukemia
analyzed: this case exhibited t(9;22)(q34; q l 1) and coexpressed both myeloid and B cell differentiation antigens.
Five of the 7 cases analyzed had deleted the J, segments
from both chromosomes. Because these deletions may
have contributed t o the pathogenesis of the disease w e
have attempted to define their boundaries. Using probes
that map both 5 and 3 of JH,the 3 (centromeric) boundary
of the deletions was mapped t o an approximately 30-kb
central region of the 6 0 kb between C6 and Cy3 in 10 of the
12 deleted chromosomes. In the remaining t w o chromosomes, the 3 boundary mapped to Sp. The 5 (telomeric)
boundary could not be defined. However, three cases with
biallelic deletion of J, showed biallelic deletion of the most
proximal variable (V,) (VH6and VH5-B2) genes, indicating
that the deletions spanned over 500 kb. VH5-B1 and VH5B3 were retained in germline configuration and no gross
deletions were observed using a vH3 subgroup-specific
probe, indicating that the 5' boundary mapped within the
V, locus. Unusual deletions of the portion of the IgH locus
including JH segments and the Cp and C6 genes may occur
in acute leukemias with immunophenotypic evidence of
commitment to the B cell differentiation pathway. The possible consequences of the deletions remain t o be determined. However, the clustering of the centromeric boundary of the deletions to Sw and t o a region between the
C6-Cy3 genes, a known "hot spot" for recombination, may
indicate the operation of a distinct pathogenic mechanism.
0 1993 by The American Society of Hematology.
T
informed patient consent. Mononuclear cell fractions were prepared by centrifugation over Ficoll-Hypaque( 1.077 g/cm3) (Sigma,
St Louis, MO). Cells were washed three times in ice-cold phosphatebuffered saline (PBS) before further processing. Unfractionated PB
from normal donors was used as a source of control DNA.
HE GENES encoding the receptors for antigen (Ig in B
cells and T-cell receptors [TCR] in T cells), are assembled during lymphocyte differentiation from widely dispersed DNA sequences, by somatic recombination.' The
human Ig heavy (IGH) chain locus maps to chromosome
14q32.3 and consists of variable (V,), diversity (D,), joining (JH), and constant (C,) region geneszs3Formation of a
functional IGH gene results initially from apposition of VH,
DH, and JH segment^.^ The VH-DH-JH unit may be subsequently transposed to any of the further downstream, (centromeric) C, genes through homologous recombination of
the switch regions, situated immediately 5' of the C, genes.
The C, genes located between recombined switch regions
are deleted. This process is referred to as class-switching5
Errors during the processes of creation of a VDJ unit and in
class-switching may be of central importance in the pathogenesis of some 9-cell malignancies resulting in chromosomal translocations and deregulation of genes that control
cell proliferation and differentiati~n.~.'
As part of our diagnostic assessment of acute leukemias,
we have investigated the configuration of the IGH locus
using JH and C p probes in 309 cases.'-'' We and others"~'*
have noted that some cases of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and biphenotypic acute leukemias with immunophenotypic evidence for commitment to
the B-cell differentiation pathway may have deletions of the
JH segments of either one or both chromosomes. In cases in
which adequate cytogenetic data were available it was apparent that these deletions could not be caused by simple chromosomal loss, because all cases had cytogenetically normal
chromosome 14s. Therefore, we have sought to define the
extent and the consequences of these deletions within
14q32.3 in acute leukemias. We report the preliminary data
on the mapping of the extent of the deletions.
MATERIALS AND METHODS
Patient Material
Peripheral blood (PB) and bone marrow (BM) samples were obtained at diagnosis and in three cases at remission after obtaining
Blood, VOI 82,NO 3 (August 1). 1993:pp 865-871
Immunophenotyping
Immunophenotyping was performed using a panel of monoclonal antibodies (MoAbs) to T-cell, B-cell, myeloid and non-lineagespecific differentiation antigens as previously described.*-"Analysis was performedby flow cytometry and by immunocytochemistry
to detect both cell-surface and cytoplasmic-antigenexpression. In
certain cases, immunoelectronmicroscopy was used to detect myeloperoxidase expression."
Genotypic Analysis
High-molecular-weight DNA was prepared from mononuclear
cells by conventional methods and digested to completion with restriction endonucleasesfor 2 hours at 37°C. Restriction endonucleases used in all samples were EcoRI, HindIII, and BamHI. Other
restriction enzymes used in this study included BglII, SacI, PstI,
and KpnI. DNA fragments were electrophoresed in 0.6%to 0.8%
agarose and were transferred to positively-charged nylon membranes (Hybond N+; Amersham, UK) in 1.5 mol/L NaCI, 0.25
From the Academic Department of Haematology and Cytogenetics, Institute of Cancer Research-Royal Marsden Hospital, Haddow Laboratories, Sutton, Surrey, UK.
Submitted October 22, 1992;accepted March 15, 1993.
Supported by grantsfrom the Leukaemia Research Fund ofGreat
Britain and the Kay Kendall Trust.
Address reprint requests to M.J.S. Dyer, MD, DPhil, Academic
Department of Haematology and Cytogenetics, Institute of Cancer
Research-Royal Marsden Hospital, Haddow Laboratories, Sutton,
Surrey, S M 2 SNG, UK.
The publication COSIS of this article were defayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
0 I993 by The American Society of Hematology.
0006-4971/93/8203-0005$3.00/0
865
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DYER ET AL
866
mol/L NaOH by overnight capillary transfer. Hybridizationto 32Plabeled probes was performed in 0.5 mol/L sodium phosphate, pH
7.2,10% (wt/vol) sodium dodecyl sulfate (SDS), IO mol/L EDTA in
a hybridization incubator (Techne, Duxford, UK), and washed to a
final stringency of 0.1 X SSC (SSC is 0.15 mol/L NaCl and 0.0 I 5
mol/L sodium citrate) at 65°C for 10 minutes.14 Autoradiography
was performed with intensifying screens at -80°C for 16 to 72
hours. Reprobing of filters was performed after stripping filters of
radioactive probe by 60-second exposure to 1.5 mol/L NaCl, 0.5
mol/L NaOH, and washing in distilled water.
To determine whether deletions involved one or both alleles,
filters were hybridized simultaneouslywith a probe within the IGH
locus and with D14S20, an anonymous polymorphic DNA probe
that maps to the telomere of chromosome 14,telomeric of the IGH
locus.’’ The total number of counts in each radioactive band was
calculated by placing the labeled filter in a y-particle wire-detection
system (“Autograph”; Oxford Positron, UK). The ratio of counts
(IGH/D14S20) in the test samples was then compared with the
ratio observed in DNA extracted from the PB of a normal individual.
The majority of probes used in this study are shown in Fig 1. The
derivation and full description of the genomic DNA probes used in
this study may be found in the following references: ( I ) DQ52/5’JH
clone, a BumHI-PstI 2.1-kb fragment.I6 (2) JH clone (C76R51A)
spanning JH3 to the distal HindIII site.17 (3) Cp exons I to 3
(C57R4), a 1.2-kb EcoRI fragment.18 (4) 5%6 (pCW35), a 2.0-kb
PstI fragment.” ( 5 ) YC6 (pMBW I), a I . I-kb BumHI fragment.”(6)
3’C6 (phage clone 706. I), a 17.6-kb Hind111 fragment cloned into
Charon 35.19 This clone contains approximately 11 kb of DNA
from the intervening sequences between C6 and Cy,. (7) Cy3
(pSy3h), a 0.6-kb Sac1 fragment derived from the four hinge regions of Cy, that shows only a small amount of cross-hybridization
with other Cy genes.” (8) Probe A is a 7.6-kb BamHI fragment
situated 5’ of Cy, subcloned into pBluescript from cos Ig6.21A
BumHI-HindIIIfragment (probe B) correspondingto the Iy, region
has also been derived from this cosmid.22Other probes used in this
study not shown in Fig 1 included (9) A V“6-specific probe, the
VH6gene maps approximately90 kb telomeric of JH.23
(10) A VH5subgroup-specific probe. Three VH5genes have been identified that
lie approximately 400, 900, and 1100 kb telomeric of JH.24These
correspond to 16.0-, 10.3-, and 5.6-kb fragments seen in HindIII
digests on conventional DNA bl~tting.~’
Both probes were kindly
provided by P.W. Tucker (Dallas, TX). (1 1) A VH4-subgroupspecific probe derived from a genomic B-cell chronic lymphocyticleukemia (B-CLL) DNA library (M.J.S.D. and V.J.Z., unpublished
observations, 1992)
In an attempt to exclude cytogeneticallycryptic MYC translocations involving the IGH locus, rearrangements were sought using
an MYC cDNA probe in Hind111 and BamHl restriction digests?
no rearrangements were detected.
All probes were used as gel-purified inserts and were labeled with
32P-dCTPto specific activity of 2 2 X IO9 disintegrations per minutelpg DNA by the method of ~ligo-priming.~~
When using the
706.1 probe and probe A, hybridization of repetitive DNA sequences was inhibited by prehybridization of the labeled probe to
Cot-I DNA (GIBCO-BRL, Gaithersburg, MD), according to the
manufacturer’s instructions.
RESULTS
Frequency of JH Deletions in Acute Leukemias
As part of our routine diagnostic assessment we have analyzed the configuration of the IGH locus in 309 cases of
Kb from JH
0
t
5
10
I
I
1
I
JH1-6
/
H
m l m2
1 1 1 I
I
E
I
H
C76R51A
6r
I
E
CAM
Jo
CH3
C6
CH 1 4
11 1 1 1 1
DQ52
25
I
I
cv
SP
Dag
+
20
15
N
CHI
h2 CH2
I 1
II
I
E
hl
Ill I
BBI
I
B
I 1
I I
I
B
HH
P
-
Kb approx from JH
7o
m
A
mlmZ
CH1 h 1 4 CH2-3
111 II 11B
pMBW1
B
706.1
I
B
I l l
E H E
I
E
II
BH
B
probe A
H
-
PSslJh
probe B
Fig 1. Schema of the 5 region of the human IGH locus showing the relative positions of the DNA probes used in this study. The distance
in kilobases from the 5 end of the JH region is shown. Note that in man the region between C6 and Cy3 has not yet been cloned but has been
estimated from pulsed-field data to be about 60 kb in length.23“E” denotes €coRI, ”H” Hindlll, and “B” 6amHl sites.
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867
IMMUNOGLOBULIN DELETIONS IN ACUTE LEUKEMIA
Characteristicsof Patients With JH Deletions
acute leukemia.'-'' Diagnosis was made on cytologic and
cytochemical appearances, supplemented by detailed imPatient characteristics are summarized in Table 1. The
munophenotypic analysis of both cell surface and cytoplasfollowing features are of note. Firstly, J, deletions were obmic antigen expression as previously d e ~ c r i b e d . ' ~ Bi* ~ ~ ~ ~served
*
both in pediatric and adult cases. All patients atphenotypic leukemias were defined by the concurrent
tained complete remission. Although all the adult patients
expression of multiple antigens of more than one hematosubsequently relapsed and died, both pediatric patients (papoietic lineage on individual blasts: a weighted scoring systients 2 and 6 in Table l) remain in remission 30 and 20
tem was used to differentiate reproducibly possible biphenmonths after diagnosis, respectively. Therefore, it is unotypic cases from leukemias which expressed "unexpected"
likely that JH deletions are associated with a specific progdifferentiation antigens, such as CD7+acute myeloid leukenostic subgroup. This is reflected in the cytogenetic divermia (AML) and ALL that expressed single myeloid antisity observed in these cases. All cases retained two copies of
gens.28
cytogenetically normal chromosome 14. The case of biUsing these criteria, the cases analysed comprised 210
phenotypic acute leukemia had the t(9;22)(q34;q 1 1) transcases of AML, 7 1 cases of BCP-ALL, and 20 cases of T-cell
location with rearrangement of the BCR gene detected on
precursor ALL (TCP-ALL): eight cases were considered to
conventional DNA blot; however, there was no docube biphenotypic acute leukemia.
mented antecedent chronic myeloid leukemia (CML)."
Of the 71 cases of BCP-ALL, 8 exhibited obvious deleTrisomy 21 was seen in three cases: in one case this was
tions of one or both J, segments. Four cases had deleted
associated with Down's syndrome. In our series of 7 1 cases
both alleles of JH (Table 1: cases 1 through 4), whereas 4 had
of BCP-ALL of 30 cases examined, 10 had rearrangement
deleted a single JH allele: of this latter group in only 2 cases
and/or deletion of CKgenes whereas five had rearrangement
were cytogenetic data available and therefore only 2 ofthese
of CX genes.'' However, 6 of 7 cases with JH deletions had
4 were studied in further detail (Table 1: cases 6 and 7).
rearrangement and/or deletion of the Ig light-chain genes.
One of the 8 biphenotypic leukemias studied exhibited
The somatic origin of these deletions was shown by the
biallelic deletion of ,J (Table 1: case 5). This case, which
presence of normal-sized JH fragments in DNA from remishad the cytologicappearances of an undifferentiated, Sudan
sion BM samples in cases 1, 2, and 7. Also, in case 1 it was
Black-positive AML, and coexpressed abundant myeloid
possible to derive phenotypically normal polyclonal B-cells
antigens (CDl3, CD33, and myeloperoxidase), was considby Epstein-Barr viral transformation of a remission sample
ered biphenotypic by the simultaneous expression of both
(data not shown).
CDlO and CD19 indicative of commitment to both myeloid and B cell differentiation pathways." Otherwise neiMapping the Extent of the Deletions Within the IGH Locus
ther monoallelic nor biallelic JH deletions were observed in
any of the cases of AML or TCP-ALL studied.
The extent of the deletions within the IGH locus on
Because these deletions may have contributed to the
14q32.3was mapped using the probes shown in Fig 1. Reppathogenesis of the disease, we therefore attempted to map
resentative conventional Southern DNA blots are shown in
their extent within the IGH locus in the seven cases in which
Figs 2 and 3.
cytogenetic data indicated the presence of cytogenetically
Dejnition of the 3'(centromeric) boundary. Of the 7
cases examined, 10 of the 14 IGH loci showed deletion of
intact chromosome 14.
Table 1. Summary of Data on Patients With Deletions Within the IgH Locus
5 IgH Locus
Case/
Material
Age/
Sex
1 PB/BM
2 PBlBM
3 BM
4 PB
5 PB
5 BM
6 PB
7 PB
1JIM
13/F
42/M
35/M
46/F
46/F
JF
3JIM
WCC
Cytogenetics
155
75
2.5
259
Trisomy 2 1
Hyperdiploid
Hyperdiploid
Trisomy 21
t(9;22)(q34;qll)
t(9;22)(q34;q11)
t(7;9)(~15;q13)
46,XY
87
87
35
16 0
IgL Locus
706.1
lgCK
lgCh
DID
G/R
G/R
G/R
NIT
R/R
DID
GIG
G/R
GIG
GIG
NIT
NIT
GIG
G/R
GIG
All cases with the exception of case 5 had the immunophenotypeof BCP-ALL, ie, CD19+CD1O+TdT+ clgp-. Case 5 coexpressed both myeloid and B
cell differentiation antigens as well as t(9;22)(q34;qll) and was therefore classifiedas a biphenotypic acute leukemia.'0,28PB and/or BM samples were
studied as indicated: identical results were obtained from both sources in cases 1 and 2 but in case 5 a clear rearranged Cp fragment was observed in
BM but not in the corresponding blood sample. Remission samples from patients 1, 2, and 6 showed normal configuration of JHand Ca sequences.
Trisomy 21 was associated with Down's syndrome in case 1 but not case 4: trisomy 21 was also a component of the hyperdiploidy seen in case 2.
Abbreviations: WCC, white blood cell count; D, deleted; G,germline; R, rearranged DNA fragments; NT, not tested; r and g in case 6 denote that
only faint rearranged and germline were observed in this case, suggesting that the majority of cells might in fact have undergone biallelic J,ICaIC8
deletion (see Fig. 2).
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DYER ET AL
868
A
B
BCP-ALL
BCP-ALL
*N
4
C
*-
* N
4
D
BCP-ALL
BCP-ALL
N
-N
~
23.1 Kb
>
’-
a-
>
I
16
j
I
-.
9.4
6.6
>
>
>
>
Probe
1
3
JH
6
-ma-
-1
35
1)4
i !
I
i
II
‘
*L
Case No:
>
1
I
>
1
N
1
CP
CY3
3
6
N
MYC
Fig 2. JH deletions in BCP-ALL representativeSouthem blot showing 68mHI-digested D N A s from BCP-ALL‘S (cases 1,3, and 6, Table
1) and DNAf”
unfractionated PBfrom a normal individual(denoted by ”N”) probed successively with (A) JHprobe C76R51A. (6)Cw probe
C75R4, (C) Cy3 probe pSr3h. (D) MYC cDNA probe cDIA. Note no detectableJHor Cpfragments in cases 1 and 3 and only faint band in case
6 (arrowed). (C) shows retention of Cy3 in cases 1,3, and 6 whereas (D)shows that the variation in the intensity of the signal with the Cy3
probe reflects variation in the amount of DNA loaded per lane. Fragment sizes were determined by coelectrophoresis of ’phage A cut with
Hindlll. Germline fragments and fragment sizes are denoted by horizontal bars to the right of each panel. Rearranged J, and Cp fragments
are shown by arrows.
both JH and Cp. However, two loci (cases 1 and 5 , Table 1)
retained Cp in a rearranged configuration. These rearrangements were detected in both HindIII and XbaI restriction
digests, indicating that rearrangement to Sp had occurred.
The biphenotypic leukemia had different configuration of
Cp in PB and BM samples. In the BM sample, a clear
rearranged Cp fragment was observed, whereas the same
fragment was not detected in the PB. The reasons for this
difference are obscure but may reflect continuing rearrangement. Variation in the configuration of the IGH locus between blood and BM samples has been reported previously.29
All cases with deletion of Cp exhibited deletion of all C6
sequences. No rearrangement of three probes that map to
C6 and its immediate 3‘ region was observed in any case.
Therefore, the configuration of the closest 3’ (centromeric)
CH gene was examined using a probe specific for CY^.^'
From pulsed-field data it has been estimated that Cy3 maps
about 60 kb 3’ of C623(Fig I). No rearrangements of Cy3
were detected in any of the cases with a wide range of enzyme digests. Using simultaneous hybridization with the
Cy, and a probe outside the IGH locus, quantitative imaging showed that both alleles of Cy, were retained (Fig 3).
Therefore, all deletions that involved both JH and Cp
mapped between C6 and Cy3. This region has not been
completely cloned in man. Probes to the IT, region (the
region from which transcription of Cy, initiates in the absence of class-switching22)and to a region further 5’ were
derived from a previously isolated cosmid clone, c0sIg6.~’
Again both probes retained germline configuration in a variety of enzyme digests. Isolation of further informative 5’
probes has been hampered by the presence of highly repetitive DNA.
Therefore, these data indicate that in all cases studied the
Yboundary of the deletions mapped to the central and thus
far uncloned region of about 30 kb of the 60-kb region between C6 and Cy3 or more rarely to Sp.
Dejnition ofthe 5’ (telomeric) boundary. All five cases
with biallelic deletion of JHshowed biallelic deletion of both
the 5’ region of JH and the most proximal DH region
DQ52.I6 A variety of probes were used in an attempt to
determine the telomeric boundary. Firstly, a probe outside
the JH locus that has been mapped close to the telomere of
chromosome 14 within the 14q32.3 band (D14S20”) was
used: both copies of this were retained in all cases (Fig 3).
The V, region was then investigated using probes specific
for vH3, 4, 5 , and 6 gene subgroups: these sequences are
dispersed over at least 2,500 kb on chromosome 14q32.3.24
The VH6gene is located 90 kb distal of JH and is the single
member of the subgroup: all five cases with biallelic JHdeletion showed biallelic deletion of vH6. The vH5 subgroup
contains three members, VH5-B1,B2, and B3 that map a p
proximately 1100, 400, and 900 kb telomeric of JH: these
genes correspond to bands of 5.6, 16.0, and 10.3 kb, respectively in HindIII digests on Southern blot analy~is.2~
Three
cases (cases I , 2, and 4, Table 1) with biallelic JH deletion
showed loss of the 16-kb HindIII band but retention of the
lower two bands. Similarly, probing with a vH3 subgroup
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IMMUNOGLOBULIN DELETIONS IN ACUTE LEUKEMIA
869
probes
B) le73 and D14S20
A)
1
2
3
1
2
3
23.1 >
-CP
9.4 >
6.6 >
4.4 >
Fig 3. Biallelic deletions of JHwith biallelic retention of Cy3 and D14S20. DNA from: track 1, a
case of TCP-ALL: track 2, biphenotypic acute leukemia with biallelic JH/Cr/C6deletion (case 5, Table l);
track 3,unfractionated PB from a normal
individual. DNA's were digested with Bg/ll and
probed successively with (A) Cr probe and (B)
D14S20 and C?3 probes simultaneously. The
filter labeled with both D14S20 and Cy3 probes
was placed in an "Autograph" y-particle wire detector and counted. Histograms from the areas of
interest containing both bands seen on the autoradiograph are shown in (C). These show the same
ratio of counts in both Cy3 and D14S20 bands in
all three cases indicating biallelic retention of
CY,.
specific probe, V, 26.8. showed no gross deletions of this
region (data not shown).
Therefore, these data indicate that the telomeric boundary of the deletions in cases with biallelic JHdeletions resides
within the V, locus, between VH5-B2 and VH5-B3, ie, between 400 and 900 kb distant from J H .
DISCUSSION
We have shown that a subgroup BCP-ALL (6 of 7 1 cases
analyzed in this study) and some cases of biphenotypic
acute leukemia with cytogenetically normal chromosome
14 may have deleted a crucial segment of the IGH locus at
I4q32.3. In about half the cases, the deletions involved both
alleles. Similar results have been reported recently by Beishuizen et al." From our survey ofacute and chronic leukemias it appears that such deletions occur only in acute leukemias of precursor cells that have made some commitment
to the B-cell lineage; similar deletions in the absence of structural cytogenetic abnormalities of chromosome 14 were not
observed in TCP-ALL, AML, or in a range ofchronic leukemias of mature B-cellss-'o (and M.J.S. Dyer, H.Kayano, D.
Jadayel, unpublished observations, 1993). The restricted
distribution and the clustering of deletion breakpoints to
either Sp or to the central 30-kb region between Cb and Cys
suggest that the deletions arose as a consequence of a specific mechanism operating on a subset of B-cell precursors.
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DYER ET AL
The precise extent, nature, and any possible biologic significance of such deletions await molecular cloning experiments. These experiments have so far been hampered by the
lack of probes spanning the area between C6 and Cy3and by
the highly repetitive nature of the DNA in this region. The
corresponding region in the mouse (which is also 60-kb
long) has been cloned in bacteriophage? neither coding nor
switch regions were identified and thus the functional significance, if any, of the region remains to be determined. Using
single-copy probes derived from the mouse bacteriophage
clones, we have failed to identify any homologous sequences within the human CG-Cy, region (J.M.H.,
M.J.S.D.; unpublished observations, 1992). Interestingly,
genetic linkage analysis has shown that the region between
C6 and Cys is a “hot spot” for recombination in humans.31
Unlike the B cell non-Hodgkin lymphomas, the IGH
locus is not commonly a target for chromosomal translocations in BCP-ALL.32Translocations involving 14q32.3 in
pediatric leukemias have been associated with mixed lineage cases and have been shown not to involve the JH sequences directly, leading to the suggestion that an unidentified gene of importance in leukemogenesis may reside on
14q32.3.33 Whether the deletions described here result in
the aberrant expression of other genes within the IGH locus
in the 14q32.3 chromosomal band, and whether this expression is of importance in the pathogenesis of BCP-ALL, remains to be determined.
ACKNOWLEDGMENT
We thank the following for kindly providing DNA probes: Prof
P.W. Tucker (Dallas, TX), Dr T.H. Rabbitts (Laboratory ofMolecular Biology, Cambridge, UK), Prof M.P. Lefranc (Montpellier,
France), Dr T. Honjo (Kyoto, Japan), and Dr T. Ford (Institute of
Cancer Research, London, UK). We thank the Japanese Shipbuilding Institute for kindly providing the mouse CG-Cy, bacteriophage
clones, and Dr Val Broadbent, Department of Paediatrics, Addenbrooke’s Hospital, Cambridge, UK for permission to report case 2.
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1993 82: 865-871
Unusual deletions within the immunoglobulin heavy-chain locus in
acute leukemias
MJ Dyer, JM Heward, VJ Zani, V Buccheri and D Catovsky
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