[CANCEA AESEAACH 40, 1354-1359, April 1980]
0008-5472/80/0040-0000$02.0O
Near Haploid Cell Line in Lymphoid Blast Crisis of Ph-positive
Chronic Myeloid Leukemia1
AllégriaKessous,2 Pierre Colombies,3 Jacques Pris, and Danielle Clement
Unite INSERM U.100 (A. K.], Service d'Hdmatologie et Gdndtique (P. C.] and Service d'Hdmatologie, Clinique Dieupafoy jJ. P.], Centre Hospitalier Universitaire,
Purpan, Toulouse, France
ABSTRACT
This report describes a case of lymphoid blast crisis of a
chronic myelocytic leukemia with the occurrence of a double
chromosomal population carrying a Philadelphia chromosome.
Fifty-five % of the cells have 28 chromosomes, and 36% show
the exact duplicate of the near haploid chromosome comple
ment. The similarities between this near haploid cell line and
those previously reported, as well as the presence of such
clones in acute lymphoblastic leukemia, are discussed. In the
leukemic lymphoblasts, the association of the Philadelphia
chromosome with a near haploid karyotype described so fan in
acute lymphoblastic leukemia provides further support for the
concept of a plunipotent Philadelphia chromosome-positive
stem cell common to both lymphoid and myeloid lines.
INTRODUCTION
The close association of the Ph' chromosome4 with CML is
well established and documented. This chromosome abnon
mality is usually observed in cells of myelocytic origin although
it may be found in precursors of erythrocytes,
ALL, the Ph' chromosome
was found either alone (1 , 3, 7, 8, 12, 26, 29) onwith additional
chnomosomal abnormalities (1 1, 16, 20, 23, 25). These find
ings have raised questions about the origin of the myelocytic
and lymphocytic lines which could be a plunipotent stem cell
common to these 2 cell types (4, 13, 14). We wish to report
here a new case of lymphoblastic crisis in Ph' chromosome
positive CML with the occurrence of a near haploid cell line
found in the patient's bone marrow.
A 61-year-old female was admitted to the hospital in May,
1972, with clinical and hematological diagnosis of CML, which
was confirmed by cytogenetic and cytochemical findings. The
patient underwent a complete remission with Misulban. This
treatment was temporarily discontinued due to pancytopenia
and a hypocellular bone marrow. When the peripheral blood
count returned to normal and the bone marrow became non
mocellular, maintenance chemotherapy was resumed using
1 This
work
2 Chargée
3 To
4 The
was
de
whom
requests
abbreviations
supported
Aecherche
by
INSEAM
Grant
74.5.028.1.
INSEAM.
for
used
reprints
are:
should
Ph'
be
addressed.
chromosome,
Philadelphia
chromosome;
CML, chronic myeloid leukemia; PHA, phytohemagglutmnmn;
ALL. acute lympho
blastic leukemia.
Received March 30, 1979; accepted December 20, 1979.
1354
MATERIALS
AND METHODS
Cytogenetic Studies. Chromosome analyses were carried
out on bone marrow aspirates using the direct method (28) and
on PHA-stimulated blood cultures after 48 and 72 hr of incu
bation. Chromosome identification was done by the A-banding
technique (9).
monocytes, and
megakaryocytes (6, 30). As PHA-stimulated lymphocytes of
CML patients failed to show the Ph' chromosome marker, it
was believed that CML originates from stem cell common to
myelocytes, erythnocytes, monocytes, and megakanyocytes.
Recently, several investigators reported the presence of the
Ph' chromosome either in ALL on in the lymphoblastic conver
sion of CML. In all these Ph'-positive
intermittent courses of Misulban. In June, 1977, the patient
presented with asthenia, fever, and an increase of WBC counts
to 21 ,000/cu mm with the presence of 5% blast cells in blood
smears. The bone marrow was hypercellulan with 57% blast
cells of small and large size (Table 1). The penoxidase, non
specific esterase, and sudan black reactions on the bone
marrow leukemic blasts were negative, but the neutrophil aI
kaline phosphatase and the periodic acid-Schiff stains were
highly positive. From these cytological and cytochemical ob
servations, the conversion of CML into an ALL form was estab
lished. After a 3-month remission induced with Solupred and
Oncovin, the patient relapsed again and died a few weeks later.
RESULTS
The first kanyotype study performed at the onset of the
disease and prior to any treatment revealed the presence of
the Ph' chromosome in all the scored metaphases of the bone
marrow and in 7 metaphases from PHA-stimulated blood cul
tune. No other abnormalities were found either in the 13 kary
otyped cells of the bone marrow or in the 12 analyzed meta
phases from blood culture. A second chromosome examination
was carried out while the patient was pancytopenic. The Ph'
chromosome was found in the bone marrow cells but not in
blood cultures. No other consistent modifications were ob
served. A third cytogenetic study was performed at the time of
relapse prior to any new therapy. In the bone marrow aspirates,
all cells were Ph' chromosome-positive with 2 modal chromo
somal numbers. Fifty-five % of the cells had 28 chromosomes,
and 36% had 56 chromosomes. Only 9% of the cells showed
46 chromosomes (Table 1). Kanyotype analysis by A-banding
technique revealed the following observations. In the cells with
28 chromosomes (Fig. 1, A and B), only 4 pains were found
normal, i.e. , Numbers 13, 14, 18, and 21 . The G22 pain, also
present, included one Ph' chromosome. The C6 painwas totally
absent, and one chromosome of the Ci I pain was structurally
modified (the short arm was deleted, and a segment was
translocated to the deleted end). Due to the absence of almost
one-half of a chromosome complement, it was difficult to es
tablish whether this translocated segment corresponded to a
fragment of a C6 chromosome long arm. All the other pairs
including the X group were haploid. The metaphases with 56
chromosomes showed the exact duplicate of the chromosome
CANCERRESEARCHVOL. 40
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1980 American Association for Cancer Research.
Near Haploid Ce!! Line in a Human Leukemia
U)
@
complement
0
@
0
0@
chromosome
@
CO E
@
(24),
.@
@
0
@
@
a
@
@
@‘
@
E
‘@
0
@fl
E
(I)
2
°@
,@
@.
‘-
2
@,)
cases
showed
chromosome
I-
6
-.@
,@
@
.@
.@
@
,@.
@:
N-
_1
.@)
0
the
+
normal
;22q
C9
—)
chro
in an ALL
similarities
although
were
case
some
(1 5).
More
differences
in
observed.
,- c%J
@,
@,
cell
and
both
out
line
with
our
lines
with
ALL
where
hyperdiplo
that,
was
in our
observed
present
during
study,
the
the
28-
lymphoid
blast
its
reported
cases
were
and
poor
the
observed,
prognosis
patient
one
of
with
a
(1
5,
Oshimura
near
18).
et
haploid
a!.
set
(1 8),
of
2
chro
mosomes and the other showing an exact duplicate of the near
haploid chromosome complement. Two blast cell populations,
small and large lymphoblasts, were reported in these patients.
This double blast population might reflect the presence of 2
chromosomal
populations.
This
fact
issupported
bythe
case
ofPnieto
eta!.(22)
who
found
only
the
near
haploid
clone
and
Inallthe
clones,
each
chromosome
pair
was
atleast
repre
one
lymphoblast
sented
0 .5:@@‘
presented
to point
type
tions.
z
who
crisis of CML diagnosed 5 years ago in an adult patient. Thus,
this near haploidy might have some close relationship with the
@‘
@
by
population.
one
In
normal
the
chromosome
case
of
with
Oshimuna
et
the
a!.
(1
following
8),
excep
the
Number
7
chromosome was involved in a translocation with apparently a
very limited chromosomal material loss. In our patient, the C6
@
pain was
C,) @;,@
%.-
@
t(9q
only
group
distribution
children
noteworthy
@,
@
@
@
translocation
cells,
by our
several
in
cell
CO
@
described
the
In
a
:
been
ALL
—.
@
@
@
the
haploid
retained.
chromosome
@
from
near
idy is more commonly observed (7, 10, 19, 30, 31). It is
,@
‘B
@
@
@
@
the
was
scnibed
e
@
@
@
in
The previously published clones (15, 18, 22) were all de
0
@
cells
recently, 2 other cases have been reported (18, 22). The
clinical, cytological, and cytogenetic characteristics of these 4
CO
@
few
has
@
@
the
,-
e
.@
In
c%J C')
0@
.@
cells.
The near haploid cell line described in this paper is the fourth
one reported. The first observation of such a hypodiploid clone
E
@
28-chromosome
F.- 0
0
@
the
DISCUSSION
6
@
in
resulted
but
mosome
0
_9. CsJ
E
@
found
with a normal chromosome set, it was clearly seen that the Ph'
partly,
revealed
0 .@
several
a2 E
@
‘-‘
@;
groups
the
@
missing.
similarities
chromosome
@
if not totally,
The comparison of the karyotype analysis of all such clones
C
in
distribution
are
represented
group,
all
the
spite
of
(Table
2).
by one
pains
some
differences
In all cases,
chromosome
were
haploid
in
the
B
pain.
In
of each
except
for
the
A and
the
No.
10
pair which was normal in 2 cases (15, 18), the No. 11 pair
@
@-
@
6
@
@
Ee
@
.@,
;
@
,
@
@
@:
which
:@
onpartial loss of the No. 6 paindiscussed above. In the D-gnoup
C) r@
normal,
@
@,
@
U
@
CCJ
@
and
at
present
study,
and
finally,
the
total
least
in
in
the
3
E
group,
patients.
the
The
F
No.
1 8
pairs
were
pain
was
found
haploid
in
all
cases. The No. 21 pair is normal in 3, if not all, patients, and in
the case described in this report, we observed two 22 chro
N.
In this
comparative
among
the
,@
addition
to
.@
in these
@‘ .@
0
the
mosomes,
one
ofthem
being
the
Ph1
chromosome.
For
the
X
c'J
:
@
in
and Y chromosomes, one X at least was retained in all cases.
c,J
@
normal
chromosome,
:
@
partly
chromosomes,
3 cases,if not all, showeda singleNo. 15
@.
@
is
,@ .E
a
4
analysis,
clones
these
cases
and
the
thus
observations,
also
raise
similarities
appear
the
questions
are
to
be
cytogenetic
as
to
the
too
numerous
nonrandom.
data
significance
In
reported
of the
near haploid clones in ALL occurrence.
The
association
of
3
factors,
namely,
Ph'
chromosome,
lymphoid blast crisis, and presence of a near haploid clone
thus fan reported in ALL, raised questions about the origin of
APRIL 1980
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1980 American Association for Cancer Research.
1355
A. Kessous et a!.
Table 2
Cornparative distribution of the chrornosornes in 4 nearhaploid cell
linesAuthors1A
group
groupD
group
group
group
group
group
chro
somes
1112Kessouset
23B
4
12Oshimura
al. (15)1111
5C
11
Y6 7
1
et
11Presentcase1111
a!. (18)1111
111
?Prieto
10a2a2
et al.'
chromosomes2 chromosomes7
8
1
9
1
10
2
111
13
14
1
1
1
2
111
2
2
chromosomes4
15E 16
11
17
18F
1
21
19
20G
12
11
1
21
12
11
1
21
12
chromosomes3 chromosomes2 chromosomes3
21
22Sex X
chromosomes1
1
(22)3
-@
aTheC6pairisabsent.
Asegment
ofC6chromosome
origin
might
have
been
translocated
tothedeleted
endofCl1chromosome.
b
One
element
of
this
C The chromosomes
pair
is
the
Ph'
chromosome.
in this case were not identified by banding technique.
the primary target cell in this CML. Several cases of Ph'
chromosome-positive ALL have been reported in the literature
(1, 3, 7, 8, ii, 12, 16, 20, 23, 25, 26, 27, 29). Since in a
minority of CML patients the blastic crisis was described as
having a lymphoblastic appearance (2, 4, 5, 13, 17), the Ph'
chromosome-positive ALL's were interpreted by Beard et a!.
(2) as blastic crises either of clinically nonexpressed CML or of
CML with a very short chronic phase. However, the hypothesis
of a plunipotential stem cell (common to lymphoid and myeloid
lines) as target cell in some CML's was suggested by Boggs
(4) who observed the ALL conversion of CML in 3 patients.
This hypothesis was supported by Janossy et a!. (13) on the
basis of surface marker analysis of blasts and more recently
by the observation of Prchal et al. (21 ). The patient we de
scnibed here developed at first a CML which converted in acute
lymphoblastic form 5 years later. The Ph' chromosome was
found throughout the course of the disease. Thus, this acute
lymphoblastic phase might be considered as a CML blastic
crisis of lymphoid morphology. However, the cytological and
cytochemical characteristics of the leukemic blast cells, as well
as the presence of a near haploid clone which so far has been
found in ALL, raise the possibility of a plunipotent Ph' chro
mosome-positive stem cell (common to both lymphoid and
myeloid lines) as cell origin in this leukemia. If so, this obser
vation would help to support the hypothesis of Boggs (4) and
the pattern proposed by Janossy et al. (14) concerning the cell
origin of some CML's.
ACKNOWLEDGMENTS
We thank B. Szirth and L. Allaire for their technical and secretarial assistance.
REFERENCES
1. Ayraud, N., Dujardin, P., and Audoly, P. Leucémieaigue lymphoblastique
avec chromosome Philadelphie. Role probable dune translocation 14—22.
Nouv. Presse Med., 4: 3013, 1975.
2. Beard, M. E. J., Durrant, J., Catovsky, D., Wiltshaw, E., Amess, J. L.,
Brearley, A. L., Kirk, B., Wrigley, P. F. M., Janossy, G., Greaves, M. F., and
Galton, 0. A. G. Blast crisis of chronic myeloid Leukemia (CML) I. Presen
tation simulating acute lymphoid leukemia (ALL). Br. J. Haematol., 34: 167—
178, 1976.
3. Bloomfield, C. D., Peterson, L. C.. Yunis, J. J., and Brunning, R. D. The
Philadelphia chromosome (Ph') in adults presenting with acute leukaemia:
a comparison of Ph'- and Ph'÷patients. Br. J. Haematol., 36: 347—358,
1977.
4. Boggs, D. A. Hematopoietic stem cell theory in relation to possible lympho
1356
blastic conversion of chronic myeloid leukemia. Blood, 44: 449—453,1974.
5. Canellos, G. P., DeVita, V. T., Whang-Peng, J., and Carbone, P. P. Hema
tologic and cytogenetic remission of blastic transformation
ulocytic leukemia. Blood, 38: 671 —679,1971.
in chronic gran
6. Chevernick, P. A., Ellis, L.. Pan, S., and Lawson, A. L. The Philadelphia
chromosome in in vitro colonies from patients with chronic myelocytic
leukemia. Science, 174: 1134—1
136, 1971.
7. Cimino, M. C., Rowley, J. D., Kmnnealey,A., Variakojis, D., and Golomb, H.
M. Banding studies of chromosomal abnormalities in patients with acute
lymphocytic leukemia. Cancer Res., 39: 227—238,1979.
8. Crist, W. M., Ragab. A. H., and Ducos, R. Lymphoblastic conversion in
chronic myelogenous leukemia. Pediatrics, 6 1: 560—563, 1978.
9. Dutrillaux, B., and Lejeune, J. Sur une nouvelle technique d'analyse du
caryotype humain. C. A. Acad. Sci., (Paris) 272: 2638-2641 . 1971.
10. Fitzgerald, P. H., Adams, A., and Gunz. F. W. Chromosome studies in adult
acute leukemia. J. NatI. Cancer Inst., 32: 395—41
7, 1964.
1 1. Forman, E. N., Padre-Mendoza, T., Smith, P. S., Barker, B. E., and Fames.
P. Ph' positive childhood leukemias: spectrum of lymphoid-myeloid expres
sions. Blood, 49: 549—559,1977.
12. Gibbs, T. J., Wheeler, M. V., Bellingham, A. J., and Walker, S. The signifi
cance of the Philadelphia chromosome in acute lymphoblastic leukaemia: a
report of two cases. Br. J. Haematol., 37: 447—453, 1977.
13. Janossy, G., Greaves, M. F., Revesz, T., Lister, T. A., Roberts, M., Durrant,
J., Kirk, B., Catovsky, D., and Beard, M. E. J. Blast crisis of chronic myeloid
leukemia (CML). II. Cell surface marker analysis of lymphoid and myeloid
cases. Br. J. Haematol.. 34: 179- 192, 1976.
14. Janossy, G., Roberts, M., and Greaves, M. F. Target cell in chronic myeloid
leukaemia and its relationship to acute lymphoid leukemia. Lancet, 2: 1058—
1061, 1976.
15. Kessous, A., Coberand, J., Grozdea, J., and Colombies, P. Clone cellulaire
a 27chromosomes
dans
uneleucémie
aigue
humaine.
Nouv.
Rev.Fr.
Hematol., 15: 73-82, 1975.
16. Mandel, E. M., Shabtai, F., Gaffer, U., Klein, B., Halbrecht, I., and Djaldetti,
M. Ph-positive acute lymphocytic leukemia with chromosome 7 abnormali
ties. Blood, 49: 281 —287,1977.
17. Mathé,G., Tubiana, M., Calman, F., Schlumberger, J. R.. Berumen, L.,
Choquet, C., Caftan, A., and Schneider,
M. Les syndromes de leucémies
aigues (SLA) apparaissant au cours de l'évolutiondes hematosarcomes et
des leucémieschroniques (analyse clmnique).Nouv. Rev. Fr. Hematol., 7:
543-554, 1967.
18. Oshimura, M., Freeman, A. I., and Sandberg, A. A. Chromosomes and
causation of human cancer and leukemia. XXIII. Near-haploidy in acute
leukemia. Cancer (Phila.), 40: 1143-1 148, 1977.
19. Oshimura, M., Freeman, A. I., and Sandbemg, A. A. Chromosomes and
causation of human cancer and leukemia. XXVI. Banding studies in acute
lymphoblastic leukemia (ALL). Cancer (Phila.), 40: 1161—1
172. 1977.
20. Oshimura, M., and Sandberg, A. A. Chromosomes and causation of human
cancer and leukemia. xxv. Significance of the Ph' (including unusual
translocations) in various acute leukemias. Cancer (Phila.), 40: 1149—1
160,
1977.
21. Prchal, J. T., Throckmorton, D. W., Carroll, A. J., lU,Fuson, E. W., Gams, A.
A., and Prchal, J. F. A common progenitor for human myeloid and lymphoid
cells. Nature (Lond.), 274: 590—591
, 1978.
22. Prieto, F., Badia, L., Mayans, J., Gomis, F., and Marty, M. L. Hypodiploidia
de 26 cromosomas en leucemia linfoblastica aguda. Sangre (Barc.), 23:
484—488, 1978.
23. Rausen, A. A., Kim, H. J., Burstein, Y., Rand, S., McCaffrey, R. M., and
Kung, P. C. Philadelphia chromosome in acute lymphatic leukaemia of
childhood. Lancet, 1: 432, 1977.
CANCERRESEARCHVOL. 40
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1980 American Association for Cancer Research.
Near Hap!oid Ce!! Line in a Human Leukemia
24. Rowley, J. 0. A new consistent chromosomal abnormality in chronic mye
logenous leukeemia Identified by quinacrmnefluorescence and Giemsa stain
log. Nature (Lond.), 243: 290-293, 1973.
25. SchmIdt, A., Dar, H., Santorineou, M., and Sekine, I. Ph' chromosome and
loss and reappearance of the V chromosome In acute lymphocytic leukemia.
Lancet,1:1145,1975.
26. Secker-Walker, L M., and Hardy, J. D. Philadelphia chromosome in acute
leukemia. Case report. Cancer (Phila.), 38: 1619-1 624, 1976.
27. Tanzer, J., Jacqulllat, 0., Boiron, M., and Bernard, J. Leucémieaigue
lymphoblastique sulvie tmoisans plus tard dune leucémie
myeloide chroni
que a chromosome Philadelphle. Lyon Med., 233: 31 1—31
5, 1975.
without prior in vitro or in vivo colchicine administration. Stain Technol., 37:
17—20,1962.
29. van Biervliet, J. P., van Hemel, J., Geurts, K., Punt, K., and Beer-van Wering
de E. Philadelphia chromosome in acute lymphocytic leukemia. Lancet, 2:
617, 1975.
30. Whang-Peng, J., Dnutsen, T., Ziegler, J., and Leventhal, B. Cytogenetic
studies in acute lymphocytic leukemia: special emphasis in long-term sum
vival. Med. Pediatr. Oncol., 2: 333—351
. 1976.
31 . Zuelzer, W. W., Inoue, S., Thompson, A. I., and Ottenbreit, M. J. Long-term
cytogenetic studies in acute leukemia of children; the nature of relapse. Am.
J. Hematol., 1: 143-190, 1976.
28. Tjlo, J. H., and Whang, J. Chromosome preparation of bone marrow cells
APRIL 1980
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1980 American Association for Cancer Research.
1357
flSS
jT
S
3
I:
B
A
I
6
8
7
11
C
4,
41@A
13
14
I-
W
a16
15
D
19
20
E
21
22
G
F
1A
18
17
xx
Fig. 1. Karyotypes established from R-banded metaphases with 28 chromosomes.
1358
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1980 American Association for Cancer Research.
».
λ*
»s*
B
4
A ¿t A
10
11
12
*
13
14
J9
20
F
15
16
_21
22_
G
•*
17
18
t
XX
1B
APRIL
1980
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1980 American Association for Cancer Research.
1359
Near Haploid Cell Line in Lymphoid Blast Crisis of Ph1-positive
Chronic Myeloid Leukemia
Allégria Kessous, Pierre Colombies, Jacques Pris, et al.
Cancer Res 1980;40:1354-1359.
Updated version
E-mail alerts
Reprints and
Subscriptions
Permissions
Access the most recent version of this article at:
http://cancerres.aacrjournals.org/content/40/4/1354
Sign up to receive free email-alerts related to this article or journal.
To order reprints of this article or to subscribe to the journal, contact the AACR Publications
Department at [email protected].
To request permission to re-use all or part of this article, contact the AACR Publications
Department at [email protected].
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1980 American Association for Cancer Research.