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[Cancer Research 60, 2775-2779, June 1, 2000]
© 2000 American Association for Cancer Research
Deletion of 6q16-q21 in Human Lymphoid Malignancies: A Mapping and Deletion Analysis1
Amanda Jackson2,
Paola Carrara2,
Veronique Duke,
Paul Sinclair,
Mary Papaioannou,
Christine J. Harrison and
Letizia Foroni3
Laboratories of Cytogenetics and Molecular Genetics, Department of Haematology, Royal Free and University College School of Medicine, London NW3 2QG, United Kingdom
 |
ABSTRACT
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Two distinct regions of minimal deletion (RMD) have been identified at
6q25-q27 in non-Hodgkin’s lymphoma (RMD-1), and at 6q21-q23 in acute
lymphoblastic leukemia (ALL; RMD-2) by loss of heterozygosity and
fluorescence in situ hybridization studies. In
this study, 30 overlapping yeast artificial chromosomes (YACs), 1
expressed sequence tag, and 11 novel YAC ends were identified
using bidirectional YAC walks between markers D6S447 (proximal) and
D6S246 (distal) in RMD-2. The genes AF6q21, human
homologue of the Drosophila tailless
(HTLX), CD24 antigen, the Kruppel-like
zinc finger BLIMP1, and cyclin C (CCNC),
previously mapped to 6q21, were accurately positioned in a
telomere-to-centromere orientation. Approximately 3.5 Mb were found to
separate the BLIMP1 (adjacent to D6S447) and
AF6q21 genes (telomeric to D6S246). Deletions of 6q were
investigated in 21 cases of ALL using the newly characterized YAC
clones in dual-color fluorescence in situ hybridization
studies. A region centromeric to D6S447 (containing marker D6S283) and
a region telomeric to marker CHLC.GGAT16CO2 (and containing marker
D6S268) were identified as distinct and nonoverlapping regions of
deletion in ALL.
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Introduction
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Abnormalities of the long arm of chromosome 6 (6q) involving the
chromosomal regions 6q16-q27 have been reported in a variety of
hematological malignancies and solid tumors (1, 2, 3, 4, 5, 6, 7, 8, 9, 10)
. The
location and extent of deletions in lymphoid malignancies vary
according to the disease type, whether B or T cell immunophenotype, and
the technique used, for example,
FISH4
or LOH. The accurate characterization of 6q deletions is of clinical
importance in lymphoid malignancies because they are related to
prognosis (10
, 11)
. Two distinct RMD have been identified
at 6q25-q27 in non-Hodgkin’s lymphoma (RMD-1) and at 6q21-q23
in ALL (RMD-2) by LOH and FISH. This study focused on the molecular
definition of a commonly deleted region between markers D6S447 and
D6S246 in RMD-2 (5, 6, 7, 8, 9, 10)
in an attempt to identify
candidate tumor suppressor genes within this region. A number of genes
have been localized to 6q21: the B-cell surface marker CD24
(12)
; the cyclin C gene (13)
; the human
homologue of the Drosophila tailless gene (HTLX;
Ref. 14
); a member of the Kruppel-like zinc finger family,
BLIMP1, the ß-IFN gene positive regulatory domain
I-binding factor (15)
; and the AF6q21 gene,
which was discovered as a result of its involvement in the
t(6;11)(q21;q23) (16
, 17)
. To evaluate the role of any one
of these genes as candidate tumor suppressor genes in patients with 6q
deletions, their precise localization was paramount.
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Materials and Methods
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Cytogenetic and FISH Analysis of 6q Deletions.
Metaphases from bone marrow samples of 21 patients with ALL and
phytohemagglutinin-stimulated cultured blood lymphocytes from normal
individuals were prepared and G-banded for cytogenetic analysis using
standard procedures. Karyotypes were described according to the
International System for Human Cytogenetic Nomenclature. DNA probes for
FISH were labeled indirectly with biotin-16-dUTP or digoxigenin-11-dUTP
(Life Technologies, Inc.) or directly with Spectrum Red,
Spectrum Green (Vysis Ltd.), or Chromatide Alexa 532-5-dUTP (Molecular
Probes Inc.). Biotinylated probes were detected with green (FITC) and
digoxigenin-labeled probes with red (Texas red) fluorescence labeled
reporter molecules. Directly labeled probes were prepared using a
Comparative Genomic Hybridization Nick translation kit (Vysis
Ltd.) according to the manufacturer’s instructions. Hybridization and
washing procedures were conducted as described previously
(18)
. Dual-color FISH was carried out using pairs of
biotin- and digoxigenin-labeled YAC DNA probes hybridized to metaphases
from patients with deletions of 6q. The extent of the deletions was
determined by mapping the retention and loss of red and green probe
signals in serial dual-color hybridizations. The presence of a normal
chromosome 6 with evidence of both red and green signals in each cell
was used as an indicator of hybridization efficiency. Deletion was
defined by loss of signal in a minimum of five cells and not less than
20% of the total observed. A minimum of 10 metaphases were scored for
each patient. The relative positions of YAC and PAC probes were
determined by dual- or triple-color FISH on interphase cells or
extended DNA prepared from cytospins of granulocytes isolated from
normal peripheral blood.
DNA Preparation from YAC, PAC, and Vectorette Library
Preparations.
High-molecular weight DNA was prepared from a 72-h yeast culture using
phenol-chloroform extraction (14)
. The sequences of YAC
ends were obtained using the PCR products of Vectorette libraries
prepared as described previously (19)
. All sequences were
checked against database sequence repositories. Primers derived from
YAC ends were tested for chromosome 6-specific amplification using
chromosome 6 hybrid DNA (MRC Resource Center, Hinxton, United Kingdom).
Novel and overlapping YAC clones were identified using PCR screening of
the Zeneca YAC library according to the protocol recommended (MRC
Resource Center). Alternatively, YAC ends were used to generate probes
for hybridization to the CEPH library.
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Results and Discussion
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YAC Mapping of 6q21.
A partial YAC contig map of RMD-2 was generated by bidirectional
cloning, using specific proximal (D6S447) and distal (D6S246) markers.
Two large previously described contigs, WC6.13 and WC6.14, were
identified (through the GDB
database5
) using 12 known markers (D6S246, D6S278, D6S268, CD24,
D6S1592, CHLC.GGAT16CO2, CHLC.GGAT14A05, D6S1296, D6S447, D6S1592,
D6S301, and D6S283). WC6.13 is proximal, is composed of 119 YACs and
spans the markers D6S1288 (proximal) and CHLC.GGAT16CO2 (distal).
WC6.14 is distal, is composed of 211 YACs, and spans the markers D6S268
(proximal) and D6S474 (distal). Y853b7 delineates the distal end of the
WC6.13 contig and extends from marker D6S447 to CHLC.GGAT16CO2. Y856e1
contains D6S246 and D6S268 and overlaps with Y916c5, which defines the
proximal end of WC6.14. Thus, Y853b7 was used to initiate the distal
walk toward the D6S246 marker and Y916c5 to walk in the centromeric
direction toward D6S447.
Bidirectional walking was also applied to an additional eight YAC
clones (Fig. 1
, 
). Eleven new STSs, 1 EST (Table 1
,
856e1-L) and 16 YAC clones were identified (Fig. 1
) in centromeric and
telomeric directions. Thus, the distance between CD24 and the telomeric
end of Y856e1 was determined to be 
1.5 Mb. Similarly, the distance
between the ends of Y830d9 and Y853b7 was estimated to be 2 Mb. Our
data therefore suggested that the distance between markers D6S246 and
D6S447 was not less than 3.5 Mb, larger than initially postulated
(10)
. No overlap between clones 36CB11 (distal) or 860e12,
860f10, and 760d2 (proximal) was demonstrated by FISH or PCR.
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Fig. 1. Overlapping YAC contig of 6q21. YAC contig map of human
chromosome 6 between DNA markers D6S1592 and D6S246. YACs are depicted
as horizontal lines with their STS content (•). The
size of each YAC is indicated (when available). YAC ends that have been
sequenced as part of this study are indicated by . The positions of
the gdb contigs (W6C13 and W6C14) are illustrated by horizontal
arrows. The existing genomic gaps are indicated by two
forward slashes.
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Gene Localization within 6q21.
The HTLX gene had been localized previously to Y28CD7,
containing marker D6S246 (Fig. 1
; Ref. 14
). The surface
antigen CD24 was mapped to a 100-kb region of Y3GA3, and it was also
contained within Y916c5. Primers from the COOH-terminal region of the
AF6q21 gene (Ref. 16
; Table 1
) were used to
screen and isolate a positive clone from the libraries developed by
Zeneca (Y8CE4; Fig. 1
and Fig. 2
a). FISH on extended DNA showed this clone to overlap with
Y856e1. In addition, clones distal to Y856e1 (Y950a8, Y846d8, Y776a5,
and Y953c2) were found to contain AF6q21 sequences by PCR,
whereas clones proximal to Y856e1 (Y28CD7, Y37ED8, and Y916c5) were
negative. This confirmed the localization of the AF6q21 gene
distal to HTLX and D6S246. CD24, HTLX,
and AF6q21 were mapped within a contiguous region of 1.5
Mb. The BLIMP1 gene had been localized previously to
6q21-q22.1 adjacent to D6S447 (15)
on clone Y665f3 (780 kb
in size), which was described to contain D6S447, BLIMP1, and
D6S268 (15)
. This suggested a physical link between D6S447
and D6S246. However, in our study BLIMP1 sequences were
detected on Y830d9 and Y900f10 but not on Y860f10, Y860e2, Y916c5,
Y856e1, or Y28CD7. Y665f3 was positive for D6S268 but not D6S447 or
BLIMP1, as suggested previously (15)
. This
restricted the position of BLIMP1 proximal to D6S447 and
confirmed the position of Y665f3 distal to CD24. Finally,
the PAC clone P13743, containing CCNC (a kind gift from Dr.
J. E. Lahti), was positioned by triple-color FISH analysis relative to
Y748c8 and PAC clone dJ202B13 (corresponding to the marker D6S1060;
Fig. 2b
). FISH demonstrated the relative order to be as
follows: centromere, dJ202B13, P13743, Y748c8, with no evidence of
overlap between P13743 and YAC 748c8. This was confirmed by the lack of
PCR amplification using primers for CCNC and DNA from
Y748c8, ruling out the proximity of CCNC to D6S283. The
region containing D6S283 has been the focus of several investigations
by LOH analysis. Merup et al., (8)
mapped the
minimally deleted region (500 kb) between markers D6S1709 and
D6S434, centered around D6S283. Y748c8 is 1.78 Mb in size. It
contains all three markers and does not contain or overlap with clones
containing CCNC. Therefore, this gene must be located
proximal to D6S283 (Fig. 2b
), outside the small deletion
described by Merup et al. (8)
. Studies by Li
et al. (13)
had previously ruled out a major
role for CCNC as a tumor suppressor gene in ALL. Despite the
detection of CCNC in 90% of patients with a visible
cytogenetic deletion or rearrangement involving 6q21, the authors found
no mutations by single-strand conformation polymorphism within the
coding region or flanking intronic sequences on the retained allele in
patients heterozygous for a CCNC deletion. Thus, they
concluded that either haploinsufficiency of the cyclin C protein
promoted tumor formation or that a tumor suppressor gene was linked to
the CCNC locus.
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Fig. 2. FISH analysis using YACs and PAC clones. Representative
FISH images: a, Y856e1 (green) and Y8CE4
(red; containing AF6q21) hybridized to
extended DNA prepared from a normal individual, demonstrating that the
two clones are partially overlapping; b, clone P13743
(orange; containing the CCNC gene) is
mapped to a position between Y748c8 (red) and PAC clone
DJ202B13 (green) using three-color FISH on normal
interphase cells; c, Y860f10 (green) and
Y830d9 (red) hybridized to a metaphase cell from patient
15, demonstrating retention of both probes on the deleted chromosome 6;
d, Y36CB11 (green; deleted) and Y830d9
(red; retained) hybridized to metaphase cells from
patient 15; e, Y38IC6 (green; deleted)
and Y830d9 (red; retained) hybridized to metaphase cells
from patient 17; f, Y856e1 (green) and
19IF11 (red) hybridized to metaphase cells from patient
17, demonstrating that a distal inversion accompanies deletion of 6q in
this case.
|
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FISH Analysis of Patients with Cytogenetically Visible 6q Deletion.
FISH analysis was carried out on a series of ALL patients with
cytogenetically detectable 6q21 deletions. A panel of probes localized
to the proximal (Y748c8, Y830d9, and Y860f10) or distal (Y36CB11,
Y856e1, Y28CD7, and Y8CE4) regions were used in combination with more
centromeric (Y38AH1 at 6q14) and telomeric (Y19IF11 at 6q25) clones.
The results are summarized in Fig. 3
. Y36CB11 was the most proximal clone within the distal WC6.14 contig,
and Y860f10 represented the most distal clone from the proximal WC6.13
contig. In 13 patients (Fig. 3
, patients 1–13) the 6q
deletion encompassed both markers D6S447 and D6S246. In patients 1–10,
deletions extended beyond and included markers D6S283 and D6S246. In
two patients (Fig. 3
, patients 14 and 15),
deletion of Y36CB11 was associated with the retention of Y830d9
(containing marker D6S447), including the most distal Y860f10 (tested
in patient 15; Fig. 2 and d
). In four patients
(Fig. 3
, patients 17–20), probes containing markers D6S447
and D6S246 were retained, whereas loss of signal was observed for
clones containing D6S283 (Fig. 3
, patient 18) and more
proximal clones (Fig. 3
, patients 17, 19, and
20). In one patient (patient 21), the results of FISH
analysis were consistent with the coexistence of two cell populations,
both carrying 6q deletions (Fig. 3
, 21a-b). A proximal 6q
deletion extended between Y38AH1 (6q14) and Y748c8 (containing marker
D6S283), whereas Y830d9 (containing marker D6S447) was retained. This
pattern of hybridization was present in 95% of cells. Within this
clone, 15% of the cells displayed an extension of the deletion
detected by the absence of signals for the clones Y830d9, Y856e1, and
Y811d4 (6q21). Y19IF11 (6q25) was retained in all cells examined. It is
plausible to postulate karyotypic evolution occurring in this patient
in the form of sequential deletion of 6q.
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Fig. 3. Patient analysis using a panel of YAC clones identified
by this study. On the left a diagram illustrates the
G-banding of the chromosome 6 q arm. Relevant
markers and the list of YAC clones used
for analysis are listed in vertical order from the centromere
(top) to the telomere (bottom). Patients
results are given in a vertical order.  , retained YAC; •, deleted
YAC. The two subclones identified in patient 21 are given as clone
21a-b, one next to the other. (See "Results and
Discussion" for further information).
|
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Conventional cytogenetic analysis revealed the same highly complex
karyotype in all cells with the 6q deletion. The extended 6q deletion
could not be differentiated from the smaller deletion by G-banded
analysis. FISH revealed a cryptic complex rearrangement in patient 16.
In this case, a proximal deletion was accompanied by inversion of part
of distal 6q, resulting in the reversed order of the two YACs 856e1 and
19IF11, from centromere:856e1:19IF11:telomere to
centromere:19IF11:856e1:telomere (Fig. 2 and f
). Discrepancies were found in the breakpoint assignments
between G-banded and FISH results in four additional patients (patients
2, 13, 18, and 20). A range of deleted subregions has been identified
within the chromosomal region 6q14-q21, in a variety of acute and
chronic lymphoid diseases, that may be related to the different
methodologies used or the types of patients included in each series
(5, 6, 7, 8, 9, 10
, 20)
. However, it cannot be excluded that a single
gene with large intronic sequences may span different areas of 6q. It
may be significant that the most proximal region was identified in a
study of adult T-cell leukemia, whereas the more distal regions were
found predominantly in childhood B-cell leukemias and in 7% of chronic
lymphocytic leukemia patients (7, 8, 9, 10
, 20)
. It is
therefore possible that the loss of two different genes in this region
may be associated with different types of lymphoid malignancy. The true
extent and precise localization of a deletion may also be masked by
other associated cryptic rearrangements involving the same chromosome
arm. Noncontiguous deletions of 6q have been reported in patients with
lymphoid malignancies and deletions have been found in association with
inversions of distal sequences, including one patient in this study
(patient 17; Refs. 9
, 11
).
In conclusion, this investigation confirms the presence of two discrete
and independent regions of deletion in 6q16-q21, one proximal and one
distal to D6S447. The former region overlaps with a restricted area of
minimal deletion in one patient described recently by Merup et
al. (9)
, and a more proximal region described by
Hatta et al. (6)
. This study has
considerably reduced the extent of the previously described deletion
distal to D6S447 (8
, 10
, 11)
, and this region will remain
the focus of further investigations, particularly the gap between
CHLC.CGAT16002 and CD24.
|
Acknowledgments
|
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We thank Dr. J. E. Lahti from the Department of Cell Biology,
St. Jude Children’s Research Hospital, Memphis, TN for kindly
providing the clone containing the CCNC gene, and Dr. B. H.
Czepulkowski from the Hematology Department, King’s College Hospital,
London for providing material from patient 17. We would also like to
thank Professor A Madrigal for constructive comments and criticisms
during the preparation of the manuscript.
|
FOOTNOTES
|
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Kay Kendall
Leukaemia Fund (to A. J. and P. C.) 
2 These two authors have equally contributed to
this study.
3 To whom requests for reprints should be
addressed, at Laboratories of Cytogenetics and Molecular Genetics,
Department of Haematology, Royal Free and University College School of
Medicine, Pond Street, London NW3 2QG, United Kingdom.
4 The abbreviations used are: FISH, fluorescence
in situ hybridization; LOH, loss of heterozygosity; RMD,
region(s) of minimal deletion; ALL, acute lymphoblastic leukemia; YAC,
yeast artificial chromosome; PAC, plasmid amplified chromosome; STS,
sequence-tagged site; EST, expressed sequence tag.
5 Available at http://www.gdb.org.
Received 8/16/99.
Accepted 4/12/00.
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ABSTRACT
Introduction
