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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 3 (February 1), 1998:
pp. 1008-1015
17p Deletion in Acute Myeloid Leukemia and Myelodysplastic
Syndrome. Analysis of Breakpoints and Deleted Segments by Fluorescence
In Situ
By
Valérie Soenen,
Claude Preudhomme,
Christophe Roumier,
Agnès Daudignon,
Jean Luc Laï, and
Pierre Fenaux
From the Laboratoire d'Hématologie, Service de
Cytogénétique, and Service des Maladies du Sang, Centre
Hospitalier Universitaire, Lille; Inserm U124 Institut de Recherche sur
le Cancer, Lille; and Département
d'Hématologie-Cytogénétique, CH Valenciennes,
France.
 |
ABSTRACT |
Recently, we and other groups reported in acute myeloid leukemia
(AML) and myelodysplastic syndrome (MDS) a strong correlation between
cytogenetic rearrangements leading to 17p deletion, a typical form of
dysgranulopoiesis combining pseudo-Pelger-Huët hypolobulation and
small vacuoles in neutrophils, and p53 mutation. To gain further
insight into this "17p-syndrome," we studied 17 cases of AML and
MDS with 17p deletion by whole chromosome painting (WCP) and
fluorescence in situ hybridization (FISH) with probes spanning the 17p
arm, including a p53 gene probe. Cytogenetically, 15 patients had
unbalanced translocation between chromosome 17 and another chromosome
(chromosome 5 in nine cases and unidentified chromosome -add 17p- in
three cases), one patient had monosomy 17, and one had i(17q). All
rearrangements appeared to result in 17p deletion. Sixteen patients had
additional cytogenetic rearrangements. WCP analysis confirmed the
cytogenetic interpretation in all cases and identified one of the cases
of add 17p as a t(17;22). WCP also identified chromosome 17 material on
a marker or ring chromosome in two cases of t(5;17). FISH analysis with
17p markers made in 16 cases showed no deletion of the 17p markers
studied in the last two patients, who had no typical dysgranulopoiesis;
p53 mutation analysis in one of them was negative. In the 14 other
cases, FISH showed a 17p deletion of variable extent but that always
included deletion of the p53 gene. All 14 patients had typical
dysgranulopoiesis, and all but one had p53 mutation and/or
overexpression. These findings reinforce the morphologic, cytogenetic,
and molecular correlation found in the 17p- syndrome and suggest a
pathogenetic role for inactivation of tumor suppressor gene(s) located
in 17p, especially the p53 gene.
| |
INTRODUCTION |
MYELODYSPLASTIC syndromes (MDSs) are
clonal bone marrow stem cell disorders characterized by ineffective
hematopoiesis leading to blood cytopenias and by a high incidence of
progression to acute myeloid leukemia (AML).1,2 Nonrandom
chromosomal abnormalities resulting in 17p deletion are seen in 3% to
4% of AML and MDS cases.3-6 They include unbalanced
translocations between 17p and another chromosome, mainly chromosome 5, and less often monosomy 17, i(17q), or del 17p. Most of those patients
have several other cytogenetic abnormalities, and about 30% of the
cases are therapy-related.7 We found a strong correlation
in AML and MDS between 17p deletion and a typical form of
dysgranulopoiesis combining pseudo-Pelger-Huët hypolobulation and
the presence of small vacuoles in granulocytes.6,7 We also
found a strong correlation between 17p deletion and p53 mutation,
suggesting that MDS and AML with 17p deletion constitute a new
morphologic-cytogenetic-molecular "entity" in those
disorders.8,9 Our results confirmed a previous report that
found a correlation between 17p deletion (mainly through i(17q)) and
pseudo-Pelger-Huët hypolobulation in blast crisis chronic myeloid
leukemia (CML),10 a situation where p53 mutation is also a
frequent event, generally correlated to 17p deletion.11
Finally, the correlation between 17p deletion and
pseudo-Pelger-Huët hypolobulation in MDS was recently confirmed
by another group.12
In our description of MDS and AML with 17p deletion, all chromosomal
studies were made by conventional cytogenetic analysis. To study more
precisely the chromosomal segments involved in those rearrangements, we
studied by whole chromosome painting (WCP) and fluorescence in situ
hybridization (FISH) 17 cases of AML and MDS where 17p deletion was
observed by conventional cytogenetics.
Fig 1C, 2C, 3C. Partial karyotypes showing rearrangements of
chromosome 17 (arrow).
Fig 1A, 2A, 3A. Whole chromosome painting (WCP) with
cyanine-3-labeled probe for chromosome 17 and FITC-labeled probes for chromosome 5 (Fig 1A and 2A), or chromosome 12 (Fig 3A). Fig 1B, 2B,
3B. FISH analysis with a Spectrum green-labeled probe for chromosome
17 centromere (D17Z1) and with a Spectrum orange-labeled probe for the
p53 gene.
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SUBJECTS AND METHODS |
Patients.
Seventeen cases of MDS and AML where conventional cytogenetics showed
chromosome abnormalities leading to 17p deletion, diagnosed at our
institution between 1987 and 1996 according to French-American-British criteria,13 and for whom adequate material was available
were studied.
Their characteristics at diagnosis are shown in Table
1. Six patients had AML, and 11 had MDS.
Nine cases were therapy-related. A review of bone marrow slides was
made for the analysis of myelodysplastic features, particularly
dysgranulopoiesis. Conventional cytogenetic analysis was performed on
bone marrow cells, after short-term (24 hours) culture without
stimulation. Chromosomes were identified by RHG and GTG banding and
classified according to the International System for Human Cytogenetic
Nomenclature.14 Hematologic and cytogenetic findings for
three of the patients were included in a previous report.7
WCP.
WCP was performed in the 17 cases on metaphase spreads with cyanine-3
(Cy-3)-labeled WCP chromosome 17 probe and with fluorescein isothiocyanate (FITC)-labeled WCP probes for chromosomes 5, 7, 12, 18, 21, and 22 (Biovation, Aberdeen, UK). Hybridization was performed
according to the manufacturer's protocol.
Slides were counterstained in Vectashield anti-fading medium (Vector
Laboratories, Burlingame, CA) containing
4,6-diamino-2-phenylindole-dihydrochloride ([DAPI] 0.2 µg/mL).
FISH analysis with chromosome 17 markers, including the p53 gene.
To determine the extent of 17p deletion and whether the p53 gene
located in 17p13.1 was deleted, we performed FISH analysis, in 16 of 17 cases with 3 yeast artificial chromosomes (YACs), 961 F10, 904 B5, and
914 C7, localized in 17p11.2, 17p11.2, and 17p12,15
respectively, and with two probes specific for p53 and Miller-Dieker
syndrome (MD) genes localized in 17p13.1 and 17p13.3, respectively. A
chromosome 17 centromeric probe (D17Z1) and, in patients with t(5;17),
a chromosome 5 centromeric probe (D5Z2) were also used. YACs were
obtained from the Centre d'Etude du Polymorphisme Humain (Paris,
France, courtesy of Dr D. Le Paslier), D17Z1 and p53 probes were from
Vysis (Woodcreek Drive, IL), and MD and D5Z2 probe were
from Oncor (Gaithersburg, MD).
Total yeast DNA was labeled by nick-translation with biotin-16-dUTP
(Boehringer, Mannheim, Germany), and unincorporated nucleotides were
removed on G50 Sephadex columns. The metaphase slides were first
treated with RNase A and pepsin as described by Wiegnant et
al.16 Hybridization was performed as described by Chaffanet et al.17 Briefly, the slides were denatured and hybridized
at 37°C with 1 µg labeled probe in the presence of 30 µg human
Cot 1 DNA (Boehringer) and 50 µg salmon sperm DNA (Sigma, St Louis, MO). Detection of the hybridized YAC probes was performed by indirect immunofluorescence using FITC-conjugated avidin (Vector Laboratories) in combination with biotinylated goat anti-avidin (Vector
Laboratories). Vectashield anti-fading medium (Vector Laboratories)
containing propidium iodide (0.4 µg/mL) was applied to the slides to
stain double-stranded DNA.
D5Z2, D17Z1, p53, and MD probes were hybridized according to the
conditions of the manufacturer. D17Z1 and p53 probes were directly
labeled by Spectrum green and Spectrum orange, respectively. D5Z2 and
MD probes were labeled by digoxigenin and detected by the
FITC-conjugated antidigoxigenin (Oncor). DNA was counterstained with
DAPI (0.2 µg/mL).
Fluorescence signals were visualized on a Zeiss Axioskop
epifluorescence microscope (Zeiss, Oberkochen, Germany) equipped with a
double- or triple-bandpass filter. Fluorescence images were captured
using the Quips Smart Capture FISH Imaging Software (Vysis). For each
slide, 15 metaphases were analyzed, on average.
Analysis of p53 mutations.
Detection of p53 mutations was made on DNA extracted from bone marrow
cells by single-stranded conformation polymorphism (SSCP) analysis of
exons 5 to 8 of the p53 gene and/or immunocytochemical analysis
of p53 protein on bone marrow slides as previously
reported.8,18 In our experience, overexpression of
p53 by this method in MDS and AML is
always associated with a p53 gene missense mutation.18
| |
RESULTS |
Interpretation of Chromosome Rearrangements by Conventional
Cytogenetics, WCP, and FISH Analysis With Centromeric Probes
t(5;17) Translocation
Cytogenetically 9 cases (no. 1 to 9) had an unbalanced t(5;17)
translocation with a breakpoint in 17p11 in 5 cases, in 17p12 in 1 case, and in 17q11 in 3 cases; the breakpoint on chromosome 5 was in
5p11 in 5 cases and in 5q11, 5q13, and 5q23 in 1 case each (Figs 1 and
2).In the remaining patient with t(5;17) (no. 5), the translocation was
associated with an inv(5)(p11q14). Cytogenetically, the derivative
chromosome appeared to have a chromosome 17 centromere (der 17) in 6 cases and a chromosome 5 centromere (der 5) in 3 cases.
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| Fig 1.
Patient no. 3, with typical der(17) t(5;17) by GTG
banding and WCP, and loss of one p53 allele. Some chromosome 5 material was found on a marker chromosome.
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| Fig 2.
Patient no. 8, with der(5) t(5;17) by GTG banding and
WCP. Non identified chromosome material was translocated on the other chromosome 5 (add(5)). Some chromosome 5 material was also found on a
marker chromosome (mar(5)). Another marker chromosome contained chromosome 17 material which included the p53 gene (fig 2B) and other
markers studied on 17p. This marker (mar(17)) also contained chromosome
7 material. Therefore, this patient apparently had no visible deletion
of 17p material.
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| Fig 3.
Patient no. 11, where RHG banding suggested presence of
der(12) t(12;17). FISH analysis showed that chromosome 17 centromere was also present on the derivative chromosome, which was therefore a
dic (12;17). One p53 allele was deleted.
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WCP confirmed involvement of chromosomes 5 and 17 in all cases. FISH
analysis with centromeric probes for chromosomes 5 and 17, performed in
8 of the 9 cases to show the presence or absence of those centromeres
in the derivative t(5;17) chromosome, confirmed conventional
cytogenetics results in 7 cases. However, in patient no. 4, FISH
analysis showed the presence of chromosome 5 centromere and the absence
of chromosome 17 centromere on the derivative chromosome, contrary to
conventional cytogenetics, demonstrating that it was a der(5) and not a
der(17).
In patient no. 9 with t(5;17), WCP showed that the ring chromosome
contained chromosome 17 material. In patient no. 8, one marker was
shown to contain chromosome 17 and chromosome 7 material and the other
to contain chromosome 5 material (Fig 2A). In patient no. 3, chromosome
5 material was also present on a marker chromosome (Fig 1A).
Rearrangement Between 17p and Another Chromosome
t(12;17).
Two patients cytogenetically had t(12;17) but with different
breakpoints on chromosomes 12 and 17: der(17)t(12;17)(q11;p11) in
patient no. 10 and der(12)t(12;17)(p12;q11) in patient no. 11. (Fig
3A). WCP confirmed the involvement of chromosomes 12 and 17 and the
presence of a chromosome 17 centromere in patient no. 10. However, in
patient no. 11, both chromosome 12 and 17 centromeres were present on
the derivative chromosome, which was therefore a dic(12;17) (Fig 3A).
t(17;21).
One patient (no. 12) cytogenetically had der(17)t(17;21)(p11;q11), an
interpretation confirmed by WCP.
t(17;18).
In one of the patients with t(5;17) (no. 6), one mitose with
der(18)t(17;18)(q11;q23), also resulting in 17p deletion, was observed.
FISH analysis confirmed the cytogenetic interpretation.
add 17p.
In three patients (no. 13, 14, and 15), the chromosomal segment
involved in the translocation with 17p was not identified by
conventional cytogenetic analysis. In the three cases, WCP showed that
chromosome 5 was not involved. In patients no. 13 and 14 but not
patient no. 15, the derivative chromosome was shown to carry a
chromosome 17 centromere. No WCP analysis for chromosomes other than
no. 5 could be performed in patient no. 15 due to lack of available
slides. WCP analysis could be made for chromosomes 5, 18, 21, and 22 in
patients no. 13 and 14 and also for chromosomes 7 and 12 in patient no.
14. No involvement of those chromosomes in the translocation was found
in patient no. 14. In patient no. 13, the translocation could be
identified as der(17)t(17;22). Patient no. 13, in addition to a
translocation involving the 17p13 band, had lost the nonrearranged
chromosome 17 copy (Table 2).
Monosomy 17 and i(17q).
The two last patients had monosomy 17 (no. 16) and i(17)(q10) (no. 17),
respectively. In patient no. 16, WCP confirmed monosomy 17. In patient
no. 17, WCP and FISH analysis showed that the patient actually had an
idic(17)(p11), as two signals for the chromosome 17 centromere probe
were present.
Complex Cytogenetic Rearrangements
Sixteen patients had one or several additional chromosomal
abnormalities, including the presence of unidentified ring or marker chromosome(s) in 12 cases. In particular, with the exception of patients no. 10, 15, and 17, cytogenetic rearrangements resulted in
loss of part or all of the long arm of one chromosome 5. Patient no. 1 also had deletion of the long arm of the other chromosome 5.
FISH Analysis of 17p Segment
FISH analysis of 17p with three YACs and the p53 and MD probes was
performed in 16 of 17 cases. Only one signal for some or all of the 17p
probes was seen in 14 cases, and two signals for all 17p probes in the
two remaining cases, patients no. 8 and 9. In those last two patients
where, as before, WCP showed chromosome 17 material on a marker and
ring chromosome, respectively, FISH analysis therefore strongly
suggested that this material corresponded to all 17p material
translocated from the derivative (5;17), although 17p microdeletions,
undetectable with the probes used, could not be excluded.
Among the 14 other patients, only one signal was found for all 5 17p
probes in 7 cases; four of them also had loss of chromosome 17 centromere (D17Z1) signal, including the patient with monosomy 17 and 3 patients who cytogenetically had a breakpoint in 17q11. In the
remaining 7 cases, only one signal was seen: for the 4 17p distal
probes in 1 case, for the 3 distal probes in 2 cases, and for the 2 distal probes (p53 and MD) in three cases (Fig
4); in the last patient (no. 13), the
deletion involved MD probe only. (In this patient, in fact, the four
proximal 17p markers showed only one signal, whereas MD showed no
signal. This was due to the presence of both monosomy 17 and
der(17) t(17;22)(p13;q?) leading to del 17p13).
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| Fig 4.
Extent of 17p deletion analyzed by FISH using 5 markers
spanning 17p and a chromosome 17 centromeric probe (D17Z1) in the 14 patients with confirmed 17p deletion. The deletion involved the p53
gene in all cases except one, but this patient (patient no. 13) had
also monosomy 17, and therefore loss of one p53 allele. The proximal
breakpoint was in 17q in 3 patients, as shown by deletion of D17Z1
probe, and located in 17q11 by conventional cytogenetic analysis. (FISH
results in patients no. 8 and 9, where 17p deletion was not confirmed,
are excluded from this figure).
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FISH analysis was generally in agreement with cytogenetic analysis for
determination of the breakpoint on chromosome 17. However, in patient
no. 3, FISH analysis showed the breakpoint on chromosome 17 to be in
rather 17p11 rather than 17p12, in patient no. 4 and no. 15 in 17q
rather than 17p11, and in patient no. 12 and no. 14 in 17p12 rather
than 17p11.
All 14 patients with loss of 17p material analyzed by FISH had only one
signal for the p53 probe.
p53 Mutations and Myelodysplastic Features
Analysis of the p53 mutation by SSCP and/or analysis of p53
expression by immunocytochemistry could be made in 13 cases. In our
experience in AML and MDS, p53 overexpression by immunochemistry on
bone marrow slides is always associated with a p53 missense mutation.18 A mutation and/or overexpression of p53
was found in 11 cases, who all had 17p monosomy and loss of one p53
allele by FISH. No p53 mutation or overexpression was found in patient no. 8, who had no 17p deletion and no p53 deletion by FISH analysis, and in patient no. 5, although he had 17p deletion and loss of one p53
allele by FISH. In the other patient without 17p and p53 deletion by
FISH (no. 9), analysis of p53 mutation and expression could not
be made.
Dysgranulopoiesis could be assessed in 16 cases, as bone marrow blastic
infiltration was massive in patient no. 10 and no mature granulocytes
were present. Typical pseudo-Pelger-Huët hyposegmentation and
small vacuoles in greater than five percent of the granulocytes was
seen in 14 patients: 13 of them had 17p deletion and deletion of one
p53 allele (the remaining patient was not studied by FISH), 10 had p53
mutation and/or overexpression, one had no p53 mutation, and
three were not studied for p53. The remaining two patients (no. 8 and
9) had no dysgranulopoiesis and, as seen before, no 17p deletion by
FISH and (in patient no. 8) no p53 mutation or overexpression.
Finally, no dysmegakaryopoiesis typical of that observed in the
"5q-syndrome" (including the presence of large monolobulated megakaryocytes) was seen in any of the 10 patients where megakaryocytes were visible on marrow smears.
| |
DISCUSSION |
Relatively large numbers of cytogenetic rearrangements leading to 17p
deletion have been reported in AML and MDS.19 They include
monosomy 17, isochromosome 17q, and unbalanced translocations between
chromosome 17 and another chromosome. The most frequent other
chromosome involved in the unbalanced translocation was chromosome 5, followed by chromosomes 7, 12, 18, and 21, whereas other chromosomes
were rarely implicated.20-25 However, with rare exceptions,25 data were only obtained by conventional
cytogenetics and no WCP or other FISH analyses were performed.
We therefore studied WCP and FISH analysis with probes specific for 17p
in 17 cases of AML and MDS with 17p deletion by conventional cytogenetics and where adequate material was available.6
This analysis seemed important to perform because in our experience and
in the literature AML and MDS with 17p deletion generally have complex
karyotypes, with unidentified chromosome markers that could contain 17p
material, and also because the chromosomal segment translocated on 17p
sometimes cannot be identified.6,19
In the patients where conventional cytogenetics suggested unbalanced
t(5;17), t(12;17), t(17;18), or t(17;21) translocation leading to 17p
deletion, WCP confirmed the translocation between chromosome 17 and
chromosome 5, 12, 18, and 21, respectively. WCP also confirmed
conventional cytogenetic findings in one patient with monosomy 17. However, combination of WCP and FISH analysis with centromeric probes
for chromosome 17 and partner chromosomes modified the interpretation
of cytogenetic data in a few cases. In particular, one of the patients
thought to have t(12;17) by conventional cytogenetics was shown to have
dic(12;17), one patient classified as i(17q) by conventional
cytogenetics was shown to have idic(17)(p11), and one patient
classified as der(17)t(5;17) was reclassified as der(5)t(5;17).
In the three cases where the chromosome segment translocated to 17p
could not be identified by conventional cytogenetics, WCP showed that
it corresponded to chromosome 22q material in one case (no. 13). In
another patient (no. 14), the partner chromosome could not be
identified, but it was not chromosome 5, 7, 12, 18, 21, or 22. In
the last case (no. 15), only chromosome 5 could be analyzed by
WCP, ruling out t(5;17).
WCP and FISH analysis showed that in two cases of t(5;17) (patients no.
8 and 9), no 17p material appeared to be deleted. In those two cases,
WCP showed chromosome 17 material on a marker chromosome and a ring
chromosome, respectively. The presence of two copies of all 17p markers
studied, including p53, was confirmed in both patients by FISH
analysis. None of those two patients had typical dysgranulopoiesis, and
p53 mutation was not found in the assessable case. By contrast, WCP and
FISH analysis confirmed 17p deletion and loss of one p53 allele in the
remaining patients. All had typical dysgranulopoiesis, and all but one
of the assessable cases had p53 mutation and/or overexpression
(which in our experience is synonymous with the presence of a p53
missense mutation in MDS and AML).18 These findings
reinforce our previous results showing the very strong correlation in
MDS and AML between 17p deletion, a typical form of dysgranulopoiesis,
and p53 mutation.7 They bring further support to the
description of MDS and AML with 17p deletion as a specific
morphologic-cytogenetic-molecular entity.7,12
Of note, although in all but three patients cytogenetic rearrangements
led to 5q deletion, no dysmegakaryopoiesis typical of the
5q syndrome was seen. On the other hand, the typical
dysmegakaryopoiesis of the 5q syndrome has been mainly
observed in cases of isolated del(5q) and is less frequent when del(5q)
is associated with other chromosome changes, as in the cases reported
here.26 Also of note was the presence of t(9;11)(p21;q23)
in addition to t(12;17) in one patient (no. 10). This patient had
previously received anthracycline-based chemotherapy for lymphoma and
had M5AML, suggesting a typical case of therapy-related AML
occurring after agents targeting topoisomerase II.27
t(12;17) unbalanced translocation associated with the p53 mutation in
this patient was possibly a secondary genetic event. Alternatively, as
a relatively high proportion of AML and MDS cases with cytogenetic
rearrangements leading to 17p deletion are therapy-related,
antineoplastic drugs could have provoked several distinct genetic
lesions, resulting in both t(9;11) and t(12;17) translocation.
FISH analysis with YACs spanning 17p confirmed the variability of the
breakpoints and extent of the deletion of 17p, already suggested by
conventional cytogenetics. Even in t(5;17) cases, the breakpoint on
chromosome 17 was variable: the most frequent breakpoints were in
17p11, but breakpoints also occurred in 17p12, 17p13, and 17q. In the
two cases with t(12;17), likewise, the breakpoint and extent of deleted
17p material was different in each patient. However, all but one of the
patients with loss of 17p material had a breakpoint proximal to the p53
gene, which was deleted in all cases. The exception was patient no. 13, where the 17p breakpoint occurred between p53 and MD marker, situated in p13.3. However, this patient has also lost one p53 allele, through
loss of the other chromosome 17 copy. Although no FISH analysis of
chromosome 5 and chromosome 12 breakpoints was performed in this study,
cytogenetic results showed, as for 17p, variable breakpoints on these
two chromosomes. These results confirm previously published cytogenetic
data in unbalanced translocations resulting in 17p deletion, which
found breakpoints in 17p11, 17p12, or 17q11 and rarely in 17p13, and
also variable breakpoints on partner chromosomes.19
Precise analysis of larger numbers of unbalanced translocations
involving 17p and different chromosomes may in the future identify
discrete breakpoint clusters on chromosome 17, where genes involved in
leukemogenesis could be located, as in the example of the MLL
gene in 11q23 or TEL gene in 12p13. However, the variable extent of 17p deletion we observed in this study rather suggests the
presence of tumor suppressor gene(s) on 17p, inactivated by the
deletion. The p53 gene could be a good candidate, or one of the
candidate genes. Indeed, in patients with deletion of 17p material,
deletion of one p53 allele was found in all cases and mutation of the
non deleted p53 allele in all but one case. A pathogenetic role of p53
inactivation in neoplasia has been shown, especially in experiments of
gene transfer of a normal p53 gene in tumor cells with p53
inactivation, where loss of tumorigenicity was found.28 In
the case of hematologic malignancies, it is strongly suspected that p53
inactivation plays a role in the progression of CML to
AML,11 of chronic lymphocytic leukemia to Richter's syndrome, and of low grade NHL to large cell lymphoma.29 In MDS and AML, 17p deletion is associated with advanced disease, low
response to chemotherapy, and short survival.7,8,30 In
those patients, p53 inactivation could play a role in disease progression and also explain the presence of complex cytogenetic abnormalities, as p53 inactivation can generate gene instability.
We confirmed in this study the close correlation between typical
dysgranulopoiesis combining pseudo-Pelger-Huët hypolobulation and
small vacuoles in neutrophils, 17p deletion, and p53 mutation. However,
the relationship between this typical dysgranulopoiesis and p53
mutation in MDS and AML with 17p deletion is unclear. We had previously
shown that these dysgranulopoietic features did not correspond to
images of apoptosis.7 Furthermore, one would expect p53
inactivation to result in reduction rather than increase in the number
of apoptotic cells. Whether this typical dysgranulopoiesis results from
inactivation of one of several genes involved in granulopoiesis and
situated on 17p (and therefore lost by 17p deletion) will have to be
further explored.
| |
FOOTNOTES |
Submitted June 3, 1997;
accepted September 26, 1997.
V.S. and C.P. contributed equally as first authors of this work.
Supported by the Fondation contre la Leucémie, the Association de
Recherche sur le Cancer, and the Centre Hospitalier Universitaire de
Lille.
Address reprint requests to Pierre Fenaux, MD, Service des
Maladies du Sang, C.H.U., 1 Place de Verdun, 59037 Lille, France.
The publication costs of this article were defrayed 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.
| |
ACKNOWLEDGMENT |
The authors are indebted to Anne-Sophie Legrain and Dominique Pruvot
for expert technical assistance.
| |
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Abstract
Introduction
Abstract