Differences Between Malignant Blood Cells From
Induced and Spontaneous Leukemias of Mice*
J. Furth, M.D., and W. A. Barnes, M. D.
(From the Department o/ Pathology, Cornell Unit,ersity Medical College and the N e w York Hospital,
N e w Yor k , N. Y.)
(Receivcd for publication I)eccmber 11, x94o)
In order to obtain cells from induced neoplasms for
comparison with those from spontaneous neoplasms,
mice of k n o w n genetic constitution were treated with
carcinogenic chemicals. These experiments are described in the first part of this paper. A genetic
analysis of malignant blood cells of induced leukemias
made by means of transmission experiments is described in the second part. Observations with carcinoma and sarcoma cells will be presented elsewhere.
Neoplasms may result from predominantly intrinsic
genetic or extrinsic environmental factors or from a
combination of the two. There is ample evidence of
the significance of both in the genesis of neoplasms in
animals ( I 2 ) .
Transmission experiments in animals of k n o w n
genetic structure are suitable to characterize the genetic
constitution of neoplastic cells. Such experiments
m i g h t indicate a significant difference between neoplasms arising as a result of predominantly genetic
factors and those caused by predominantly environmental factors.
It has been shown recently (18) that spontaneous
leukemias arising in hybrid mice of which I parent
was from a highly leukemic stock, Ak, and the other
from a relatively nonleukemic stock, Rf, behave in
transmission experiments like leukemias arising in the
leukemic stock. They are transmissible to almost
every member of the leukemic stock and to hybrids
of the ist filial generation, but not to members of the
nonleukemic stock. This indicates that the leukemic
cells arising in these hybrids resemble genetically the
cells of the leukemic stock more closely than the cells
of the hybrids in which the disease occurs.
It seemed desirable to determine whether malignant
cells of leukemias induced in hybrids by carcinogens
possess the genetic constitution of the hybrids or that
of the ancestral leukemic stock. Neoplastic cells are
regarded as mutants by several investigators (8) and
by others as normal cells stimulated by ubiquitous
agents or viruses to unrestrained multiplication (17).
Should the neoplastic cells be mutants, their genetic
constitution m i g h t differ from that of the cells from
which they have arisen and from cells of the ancestors.
It has been shown (3, 19) that the genetic constitution
of different neoplasms arising spontaneously in the
same host may differ, but this is not true for the
spontaneous leukemias arising in Ak-Rf hybrids, the
cells of which resemble each other and the A k cells
very closely.
Incidence o/ spontaneotts neoplasms among the experimental
animals.--Mice of stocks Ak, Rf, anti of hybrid combinations
were used. Stocks Ak and Rf have becn inbred for more than
2o generations; their origin has been described by Furth, Seibold, and Rathbonc (io).
A recent preliminary analysis of the incidence of spontaneous
leukemia and tumors among the purebred and hybrid mice, to
be described more full)' elsewhere (x i), is as follows:
Number
Stock of mice
of mice
Ak . . . . . . . . . . . . . . . . . . . . . . . .
214
Rf . . . . . . . . . . . . . . . . . . . . . . . .
x67
FI (a) [Ak~xRfd'] . . . . . . . . . . 18o
FI (b) [Rf~xAkc~] . . . . . . . . . . 1 5 1
F2 [FI (a)xFI (a)] . . . . . . . . . . 238
F2 [FI (b)xFI (b) ] . . . . . . . . . .
2I 3
9
Lung
tumors,
per
cent
o
26
12
18
12
19
Most of the leukemias ill stock Ak are ot the lymphoid type;
a few are myeloid. St}ontaneous leukemia is rare in stock Rf
and the type is usually monocytic o r mycloid. Other types of
tumors are almost nonexistent among mice of stock Ak.
Lung
tumors are frequcnt among Rf mice, but other neoplasms arc
rare (2).
Transmission o/ lettkemia.---Transmission of leukemia was
attempted by injecting in the tail vein of mice 0.I cc. of a
suspension of cells from spleen or spleen and lymph nodes from
a mouse with leukemia, as described previously (Io).
EXPERIMENTAL PRODUCTION OF NEOPLASMS
The results of :4 experiments made d u r i n g a period
of 3 years are s u m m a r i z e d in Table I. Nearly every
mouse receiving methylcholanthrene or benzpyrene
developed : or several neoplasms. T h e subcutaneous
injection of the chemical resulted in the development
of sarcoma or carcinoma at the site of injection and in
an increased incidence of lung tumors. T h e data
indicate that the incidence of leukemia was increased
*This investigation was aided by grants from The Jane
Coffin Childs Memorial Fund for Medical Research, The Lady
Tata Memorial Trust, and The International Cancer Research
Foundation.
2
Lymphoid
and myeloid
leukemia,
per cent
74
2
22
12
12
I7
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Research.
Cancer Research
I8
by the subcutaneous injection of carcinogens, in the FI
and F2 hybrids.
It is also evident that the incidence of leukemia was
greatly increased by the percutaneous application of
methylcholanthrene in the relatively nonleukemic Rf
mice, and in F I and F2 hybrids, while there were
fewer cases of leukemia among the painted mice of
the leukemic stock Ak than among the controls:
.a
o
.
9~
.
r
_g
~J
+
d
lxl
9 et
el
et
et
o~
Stock of m i c e . . . . . . . . . . . . . . . . .
Ak
N u m b e r of m i c e painted w i t h
methylcholanthrene ..........
33
Percentage of l e u k e m i a . . . . . . . . .
58
N u m b e r of control mice . . . . . . . .
2i 4
Percentage of spontaneous leukemia .....................
70
k~
"~o~
<5
z
0
0
~
O0
0
o
~
++++
+++
+
ca
~ca
~e,a
r
z
~1"
m,
u~
ca~-2
9
o~
~a
ca
E~
._=.~
E
Z
-~..=
s;
~E-d
z
ca
~ c a
~ca
Zca
r
ca
ca~o
ca
O
.~-<
ell
ell
~
~
e~
,=ca~
~oca
~.~
g 1~ 1~ N
~N
ca
" ~
e~,x: ca
,
~-'~
X
g
Rf
FI
F2
32
34
I67
37
78
33I
i6
25
451
4
21
12
In order to evaluate these data it is desirable to
record the incidence of both spontaneous and induced
leukemias according to the age of the mice. Table II
shows that the peak occurrence of spontaneous leukemia in mice of Ak stock was at from 8 to 9 months
of age, whereas the treated mice died of this disease at
the age of from 4 to 5 months. All painted mice in
the experiment were dead before the age of io months.
It is evident that the chemical hastened the development of leukemia, and that a consideration of the
incidence of the disease only, without considering the
age of the experimental animals, is misleading.
Table II shows that painting mice of the relatively
nonleukemic stock Rf with methylcholanthrene hastened the development of leukemia and greatly increased its incidence. Among the painted mice of this
stock leukemia occurred at the age of from 4 to 5
months, while most spontaneous leukemias in this
stock occurred after the age of 13 months. Most
spontaneous leukemias arising in this stock were monocytic or myeloid; all induced leukemias were lymphoid.
In the ISt filial generation of hybrids between the
leukemic stock Ak and the nonleukemic stock Rf,
spontaneous leukemia occurred at a relatively late age
(Table II). The incidence of leukemia in the FI
hybrids was approximately I/3 that observed in the
leukemic stock, and most cases of leukemia occurred
after 14 months of age in comparison with a peak
incidence of from 8 to 9 months in the leukemic stock.
All but 1 painted mouse of the FI hybrids living
longer than 6 months died of leukemia. Subcutaneous
injection of carcinogens also increased the incidence of
disease and hastened its development.
The behavior of the F2 hybrids is similar to that
of the FI hybrids. Although the number of experimental n-rice is small, the data are sufficient to indicate
that both subcutaneous and percutaneous applications
of methylcholanthrene increased the incidence of leukemia and hastened its occurrence.
Downloaded from cancerres.aacrjournals.org on June 15, 2017. © 1941 American Association for Cancer
Research.
Malignant Blood Cells in Leukemias of Mice
The
data of Table
I also suggest that leukemia
more readily induced in mice of approximately
Experiment
Neoplasms other than leukemia.--h is well k n o w n that
painting of mice by carcinogens increases the incidence of lung
tumors (T, t3, i 6 ) . Our data (Table I) do not give an accurate picture of the incidence of this neoplasm because man)'
of the animals were killed or died with leukemia or with cutaneous or subcutaneous tumors at a relatively early age. Nevertheless, they are sufficient to indicate that the incidence of lung
tumors was greatly enhanced both by cutaneous and subcutaneous application of the carcinogen in all stocks studied. This
neoplasm is almost absent in our stock Ak and has not been seen
is
3 weeks
of age than in those of from 5 to 7 weeks of age.
In
i x , i 6 o f 17 p a i n t e d m i c e , 3 w e e k s o f a g e ,
had leukemia;
whereas
in E x p e r i m e n t
i o , o n l y 13 o f
20 p a i n t e d m i c e , 7 w e e k s o f a g e , h a d t h i s d i s e a s e , e v e n
though
t h e o l d e r m i c e r e c e i v e d 39 p e r c u t a n e o u s
cations
of the
chemical
TABLE II:
while
THE
the
younger
OCCURRENCE
OF
appli-
mice
19
re-
SPONTANEOUS
AND
INDUCED
LEUKEMIA
IN
RELATION
TO
AGE
Age in months
A
r3 or
Mice
less
Ak Untreated
Leukemic . . . . . . . . . . . .
Nonleukemic . . . . . . . . . . . . .
Treated
Percutaneous
Leukemic . . . . . . . . . . . . . . . .
Nonleukemic . . . . . . . . . . . . . . .
Rf Untreated
Leukemic . . . . . . . . . . .
Nonleukemic . . . . . . . . . . . . .
Treated
Subcutaneous
Leukemic . . . . . . . . . .
Nonleukemic . . . . . . . . . . . . .
)Percutaneous
Leukemic . . . . . . . . . . . . . . . .
Nonleukemic . . . . . . . . . . . . .
FI Untreated
Leukemic . . . . . . . . . .
Nonleukemic . . . . . . . . . . . . .
Treated
Subcutaneous
Leukemic . . . . . . . . . . . . . . . .
Nonleukemic . . . . . . . . . . . . . . .
Pcrcutaneous
Leukemic . . . . . . . . . . . . . . . .
Nonleukemic . . . . . . . . . . . . .
F2 Untreated
Leukemic . . . . . . . . . . . . . . . .
Nonleukemic . . . . . . . . . . . . .
Treated
Subcutaneous
Leukemic . . . . . . . . . . . . . . . .
Nonleukemic . . . . . . . . . . . . .
Percutaneous
Leukemic . . . . . . . . . . . . . . . .
Nonleukemic . . . . . . . . . . . . .
4
IO
6
6
io
4
4
5
8
. . . .
15
19
I
I
3
12
24
79
8
9
IO
II
la
4
2
4
IO
2
30
8
30
8
22
5
I
9
8
9
I
3
6
3
6
. . . . . . . . . .
2
..
4
2
6
I
I
9
6
.3
~
2
6
..
I
..
. .
IO
7
4
4
..
I
--
2
I
9.
I
. .
I
2
I
9
3
6
2
6
. .
I
I
I
. . . . . . . . . .
7
2
I
9
Over
14
7
. . . . . . . . . . .
2
3
4
9
14
6
. . . . . . . .
7
3
I
I3
5
3
7
5
16
I
o
5
4
43
I2
17
II
26
183
4
24
6
6
7
17
26
3o
33
255
6
3
12
5
5
9
2
9
2
5
5
I
x
2
3
2
6
..
IO
2
3
-.
9.
t
. .
..
3
6
4
5
8
9
8
.
.
I
.
.
.
.
.
.
.
.
* These data are incomplete; mice killed at various intervals in a study of the pathogenesis of induced leukemia are omitted.
c e i v e d o n l y 22.
In Experiment
3, l e u k e m i a
developed
in 9 o f 13 m i c e , 3 w e e k s o f a g e , r e c e i v i n g 24 p e r c u taneous applications of methylcholanthrene,
as c o m pared with io of 2o mice, 6 weeks of age, that received
34 a p p l i c a t i o n s o f t h e c h e m i c a l
number
(Experiment
of mice in the 2 experimental
a n d t h e i r a g e d i f f e r e n c e is n o t g r e a t .
age to the response of percutaneous
application
of
methylcholanthrene
2).
groups
The
The
is s m a l l
relation of
and subcutaneous
deserves
further
in mice of stock Rf before the age of approximately 8 months. In
a study on the pathogenesis of lung tumors induced by methylcholanthrene every mouse of F2 hybrids surviving 5 months of
age had puhnonary tumors. T h e number of lung tumors in
most mice of this series exceeded Joo (5).
T h e data on the incidence of cutaneous tumors (Table I) is
likewise inaccurate. T h e incidence of papillomas in the earlier
series was not faithfully recorded. In many mice, i or several
papillomas changed into carcinoma, but the character of the
cutaneous tumors has not been investigated.
study.
Downloaded from cancerres.aacrjournals.org on June 15, 2017. © 1941 American Association for Cancer
Research.
Callcgr
20
Research
spontaneously in this stock and could not be transmitted to Rf mice. Three of these 4 strains that were
tried were passed successfully to F1 hybrids. One
strain was successfully transmitted to Rf mice in 2 of
9 experiments.
Leukemias induced in stock R/.--All 3 strains were
readily transmissible to Rf mice and could also be
grafted on mice of the Ak stock; 2 with ease, and i
with difficulty. The number of successful inoculations
was greatest in the Rf stock, as great or almost as
great in the FI stock, and moderate or much less in
T R A N S M I S S I O N OF INDUCED L E U K E M I A S
The data summarized in Tables I and II indicate
that methylcholanthrene increases the incidence of leukemia and hastens its development. The question
arises whether this effect is due to a lowering of the
host's resistance to neoplastic cells which are present
in a latent state in apparently healthy animals, as
suggested by Cohnheim (7) and recently by Fischer
(9), or to a malignant transformation of normal cells.
The stocks employed, Ak and Rf, are unusually suitable for the investigation of this problem because the
'~'ABL r" l l I :
TRAN,~:SII,';SIBILITY OF
SPONTANEOUS
LEUKEMIA
*
Grafted on
Leukemia
occur r ing in
~tock A k
Stock Rf
F I hybrid
1:2 hybrid
F3 hybrid
Stock A k . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Stock Rf . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
FI hybrids ...........................
F2 h y b r i d s . . . . . . . . . . . . . . . . . . . . . . . . . . .
F 3 hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . .
Excellent
9 Failed
Excellent
Excellent
Excellent
Failed
Excellent
Failed
Failed
Failed
Excellent
Excellent
Excellent
Excellent
Excellent
Good
Fair
Variable
Fair
Fair
Fair
Fair
Fair
Fair
Fair
* l)esi.,.,nation of success of inoculation:
cent; Failed:- o per cent.
Excellent -.apl~roxinmtely r(~o per cent; Good=75 per cent; Fair
TABLE I\7:
~I'v,ANSMISSION E X P E R I M E N T S
OF
LEUKEMIAS
TNDUC:D
50 per cent; P o o r = z 5 per
BY CARCINOGEN,I;
Mice receiving injection of leukemic ceils
Ak
r
l.eukem ia
Stock
of
origin
Ak
Rf
FI
F2
Rf
r
No. of mice
];'2
No. of mice
I6
73
2
I2
92
7
78
Injeeted
+
Pe r
cent
+
12
I
8
+
72
60
94
96
9
3
6
4
62
I6
36
19
6
o
o
o
Io
o
o
o
25
27
212
8
6
8
47
32
47
40
I6
2
85
50
4
4
~
9
17
13
46
17
I2
46
Ioo
92
IOO
3
6
3
16
3~
12
I6
26
IOO
87
. . . .
3
I7
12
IOO
. . . .
Ma
I31
Ma
Ma
Ma
529
531
562
7
5
5
3
35
23
26
16
26
4
o
o
74
17
0
o
3
3
5
3
17
16
29
I6
4
o
o
o
23
o
o
o
12
5
5
4
58
26
24
I8
46
I8
79
69
2
II
. . . .
I9
I6
79
89
. . . .
. . . .
Ma
Ma
6i
62
IO
56
42
75
4
5
27
15
56
5
29
35
5
o
17
o
13
I2
72
7~
55
43
76
6I
spontaneous leukemias arising in their hybrids resemble in transmission experiments the leukemias arising in the ancestral leukemic stock (Table III) (12).
Should carcinogens bring about a malignant transformation of normal cells, it is likely that in hybrids
the neoplastic cells will resemble hybrid cells more
closely than those of either parental stock. Of 83
leukemias induced by carcinogens, attempts were made
to transmit 2o. Fourteen of these attempts were successful and the results of 13 tested genetically are summarized in Table IV.
Leukernias induced in stoc k Ak.--Three of 4 strains
of transmissible leukemia induced in Ak mice behave
in transmission experiments like those originating
4
22
. . . .
3
I3
2
9
4-
28
15
59
26
Rf f
Rff
Rf f
No. of
experi- Inments jected
No. of
experiments
39
25
63
27
+
Per
cent
+
No. of mice
Per
cent
+
7
4
11
5
Strain
No. of
experiInments jected
9
Per
cent
+
A k 946
A k 966
A k 970
A k lO3O
No. of
experiInments jected
Fr
a
No. of mice
I
.
6
.
3
3
.
.
20
23
3
.
.
.
5~
.
64
13
9
65
39
the Ak stock. Two of the transmissible strains induced
in this stock, Rff 25 and Rff 27, were likewise passed
to mice of F 3 generation. In 5 experiments made with
strain Rff 25, 2i of 29 injected mice, 72 per cent, developed leukemia. In I experiment made with strain Rff
27, 2 of 8 mice had leukemia.
Leukemias induced in FI hybrids.--Two of the 4
transmissible strains could be readily grafted on F1
hybrids but not to mice of either parental stock. A
3rd strain, on the contrary, was nonspecific and could
be grafted to members of both parental stocks, although the percentage of successful inoculation was
highest in F1 hybrids. The 4th strain could be transmitted to an occasional mouse of the ancestral leu
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Research.
Malignant Blood Cells in Leukemias of Mice
kemic stock, Ak, not at all to mice of the ancestral
nonleukemic stock, and fairly well to FI hybrids.
Thus 3 of the 4 transmissible leukemias produced in
FI hybrids differed genetically from each other as well
as from the spontaneous leukemias arising in FI
hybrids.
Leukemias induced in F2 hybrids.--One of the 2
strains behaved like the spontaneous leukemias arising
in this stock in that it could be grafted on F2 and FI
hybrids and on Ak mice, but not on Rf mice. The
percentage of successful inoculations was only moderate. The 2nd transmissible strain was nonspecific and
could be transplanted to mice of all stocks tested.
D~scussmN
These studies indicate that leukemia can be readily
produced by carcinogens in mice of stocks Ak, Rf, and
in their hybrids. Morton and Mider (14, 15) have
already shown that painting of mice of a susceptible
stock with methylcholanthrene over long periods of
time hastens the occurrence of leukemia. Brues and
Marble (6) found that painting mice of Bagg's albino
stock with a carcinogenic tar increased the incidence of
lymphoblastoma and lymphatic leukemia from 2 per
cent to 5o per cent, but similar treatment of C57 mice
failed to produce lymphomatosis. The experiments
described here indicate that the subcutaneous injection
of this chemical is likewise productive of leukemia, although painting is the more effective procedure in
producing the disease.
The leukemias induced by carcinogens are about as
readily transmissible to mice of the stocks of origin as
the leukemias arising spontaneously. Previous studies
have shown that the leukemias arising spontaneously
in the highly leukemic stock Ak cannot be transmitted
to Rf mice. The present experiments show that this
is also true for 3 of 4 induced leukemias. The 4th
strain could also be grafted on Rf mice, though with
difficulty. The spontaneous leukemia arising in the
Rf stock that was analyzed genetically (18) could be
readily grafted on Rf mice but not at all on Ak mice.
All 3 leukemias induced in this stock, on the contrary, could be grafted on Ak mice.
The critical experiment in establishing a difference
between spontaneous and induced leukemias involves
a study of this disease occurring in hybrids. All spontaneous leukemias observed in FI and F2 hybrids that
were transmitted resembled the Ak leukemias and
could be grafted on Ak mice as well as on hybrid mice,
but not at all on Rf mice. In contrast to this, none of
the 4 leukemias induced in FI hybrids was of the Ak
type. One was similar to the Ak leukemias in that it
could be grafted on an occasional mouse of this stock,
but it could be passed more readily to FI mice. Two
of the strains seemed to require genes from both
2i
parental stocks for successful transplantation, for they
could be grafted only on hybrid mice and not on mice
of either parental stock. The 4th strain, on the contrary, was nonspecific and could be grafted on mice of
all stocks tested, although the percentage of successful
inoculations was lower in Rf mice than in Ak mice.
One of the 2 strains of leukemias induced in F2
hybrids was similar to the latter, while another strain
was of the Ak type.
Spontaneous neoplasms arising in hybrids of known
genetic constitution have thus far been given little
consideration (18). Moreover, most of the spontaneous
neoplasms studied from the genetic standpoint were
breast tumors, which, in the light of recent investigations (4), can no longer be regarded as true hereditary
neoplasms.
Experiments are in progress to compare the character of spontaneous and induced neoplasms other
than leukemias. The data thus far accumulated indicate that the breast tumors induced by the extrachromosomal "nursing factor" of Little and Bittner
(4) in the Ak stock resemble in transmission experiments the neoplasms of stock Ak and not those of the
stock C3H from which the nursing factor is derived.
Spontaneous neoplasms other than leukemia are rare
in the stocks studied, and it is possible that the few
that were observed are not truly hereditary neoplasms.
Nevertheless, we have undertaken a study of the
genetic constitution of both spontaneous and induced
tumors in these stocks. The tumors induced by
methylcholanthrene in Ak, Rf, and hybrid mice differed among themselves in transmission experiments.
Some tumors induced in Ak or Rf mice were transmissible to mice of the stock in which they arose, and
to hybrids, but not to mice of unrelated stocks; others
could be grafted on both Ak and Rf mice and their
hybrids. Tumors induced in the hybrids could be
passed to neither, to one, or to both, of the parental
stocks, as well as to mice of the hybrid combination in
which they arose.
S~MMAI~Y
Leukemia was produced by the administration of
carcinogenic chemicals in mice of a leukemic stock,
Ak, in mice of a stock, Rf, in which spontaneous leukemia is rare, and in hybrids of these stocks.
The genetic structure of neoplastic blood cells from
induced leukemias was tested in transmission experiments using purebred and hybrid mice of these stocks.
Previous experiments have shown that the spontaneous
leukemias arising in these hybrids are, in transmission
experiments, similar to the spontaneous leukemias arising in leukemic stock. The present experiments have
shown that the induced leukemias differ among themselves. Only i of 6 transmissible leukemias induced in
Downloaded from cancerres.aacrjournals.org on June 15, 2017. © 1941 American Association for Cancer
Research.
Cancer Research
22
hybrids resembled closely those arising spontaneously.
Two were nonspecific and could be grafted on both
parental leukemic and nonleukemic stock, and 2, on
the contrary, could be readily grafted on hybrids but
on neither parental stock.
CONCLUSION
Leukemic cells from spontaneous and induced leukemias may differ genetically as indicated by transmission experiments. This difference may be explained
by assuming that the cells of the induced leukemias are
mutants.
Miss Mary C. Boon rendered valuable technical assistance
during the course of this study.
REFERENCES
x. ANDERVONT, H. B. Pulmonary Tumors in Mice. Pub.
Health Rep. 54:1512-I533. 1939.
2. BARNES, W. A., and R. K. COLE. The Effect of Nursing
on the Incidence of Spontaneous Leukemia and Tumors
in Mice. Cancer Research, in press.
3- BITTNER, J. J. Genetic Studies on the Transplantation of
Tumors. Am. J. Cancer I7:724"734. 1933.
4. Bn'TNER, J. J. Possible Method of Transmission of Susceptibility to Breast Cancer in Mice. Am. J. Cancer ,t9:
lO4-I 13. 194o.
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Differences Between Malignant Blood Cells From Induced and
Spontaneous Leukemias of Mice
J. Furth and W. A. Barnes
Cancer Res 1941;1:17-22.
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