From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
The
Heritable
Nature
of Clonal
Characteristics
Myeloblastic
By E. A.
Marked
patient-to-patient
blood
colony
tors
or marrow
methods
We
were
G
more
variation
change
asked
with
is
We
when
blast
study
hemopoietic
progenitor
acute
myeloblastic
leukemia
double
agan
method
growth
patterns
have
significance
applied
have
and
J. E. Curtis,
when
using
progeni-
course
of the
has
were
in
been
to
the
of Robinson
et al.,7 abnormal
been identified
and prognostic
to them.35
These
abnormal
been
observed
to become
to recur
in relapse;5
but
normal
quantitative
with
this
technique,
to vary
with
time
values
at presentation8
colony
number
was
in a manner
unrelated
or to clinical
status.6
found
either
to
for
been
proposed
as the
If a similar
mechanism
patient-to-patient
variation
in the
generators
is responsible
Vol.
58,
No.
1 (July),
1981
Using
measure
of attempted
only
nemis-
progenitor
a colony
the
assay
for
following:
by exposure
variation
As
such,
replating
in
or cytosine
of this heterogeneWe have
now
and
Table
tion
with
I contains
have
been
for
the
the
Submitted
POMP
Cancer
reprint
500
Other
Sherbourne
the
was
of Graduate
Research
and
Council
Research
Founda-
of Canada.
March
1 1, 1981.
E. A. McCulloch,
Street,
6-
studies
School
Medical
accepted
to Dr.
and
(5-Aza).
Canada.
Treatment
1980;
regimens
experimental
and
Institute
29,
requests
for
the
Cancer
arabinosyl
of prednisone.
or 5-azacytidine
Toronto,
by grantsfrom
(adriamycin,
and
consists
A
(cyclophos-
vincristine,
(6-TG)
Institute
December
AAC
methotrexate,
Cancer
presenta-
treatment.
CAV
6-mercaptopurine.
of Toronto,
National
used:
(hydroxyurea
blood
Ontario
and
seven
disease.
at each
status
vincristine),
obtaining
in part
Canada,
lnstitute,
and
Ontario
Supported
Address
and
from
of their
patients
were
HU-Ara-C
prednisone,
University
and
for the
or 6-thioquanine
the
clones.
syringes
course
of clinical
published;6’8’9
methotrexate,
protocol
the
protocols
and
high-dose
From
tion,
data
cytosine
cytosine)
Studies,
may
AML
in hepaninized
a statement
arabinosyl
cytosine)
properties
METHODS
during
of chemotherapeutic
phamide,
of
obtained
repeatedly
hematologic
with
arabinosyl
The
was
AML
together
number
AND
one occacapacity
proper-
Treatment
blood
Peripheral
these
ofindividual
MATERIALS
this
capacity
to drug in vitro.
was
again
ob-
the nature
measurements.
nature
cell
the approach
of obtainproperties
of the blast
determined
by
to adniamycin’6
patient.
intrinsic
mercaptopurine
concentrations
AML.
we now
as
sensitivity
in each
Patients
to
characteris-
studied
seven
AML
patients
on more
than
sion. Our findings
indicate
that self-renewal
and drug sensitivity
are stable
blast progenitor
the
We
sensitivities
heritable
to measuring
We investigated
making
serial
include
of myelopoietic
progenitors,
these values
would
reflect
clonality
rather
than
important
leukemia-related
abnormalities
of differentiation.
This
view
was
supported
by the clinical
observation
that
measurements
of progenitor
cell concentrations
obtained
using
the methylcellulose
method
did not contribute
signifi-
Blood,
in
oncovin,
of
are
These
evolving.
and
in outcome
arabinoside’7
determined
Marked
patient-to-patient
patients
expansion
have
heterogeneity.’3
drugs
arabinoside)
patients.
or slowly
renewal
we have taken
data
on the
for
self-renewal
culture,’5
and
of consistency
of the measurement
time,
we have
questioned
the
measurements
to cellular
processes
From
this point of view, the patient-to-patient
vaniation might
be likened
to the clone-to-clone
heterogeneity observed
when the cellular
composition
of individual
spleen
colonies
is measured.’2
In the
latter
instance,
stochastic
events
occurring
during
clonal
for
As an alternative
reflect
might
be
that hemoleukemia.”
AML
clones.
concentrations,
ing quantitative
ties
in individuals
with
relevance
of the
specific
to leuke-
cytosine
seven
to be stable
cantly
to the variance
sion induction.8
served.
ity by
and
of
capacity
in leukemic
The origin of patient-to-patient
variation
is relevant
to the interpretation
of culture
results
obtained
using
the methylcellulose
technique.
Noting
both the distnibutions
of the values
of granulopoietic
and erythropoietic
progenitors
among
AML
patients
and the lack
ma;’#{176}we have
suggested
that
the data
interpreted
in light of findings
suggesting
poiesis
may
be predominantly
clonal
in
found
population,’4
in
courses
chemotherapeutic
progenitors
data
have
not been
reported
for individual
patients
studied
repeatedly.
Marked
variation
in numbers
of
granulopoietic”6’t
on erythropoietic
colonies9
was seen
when AML
marrow
was cultured
in methylcehlulose
in
the
presence
of leukocyte
conditioned
medium
(LCM);
were
that
J. S. Senn
(adniamycin
in the
conclude
with
Using
and
sensitivity
properties
tics
used
patients
(AML).’6
drug
Messner,
repeatedly
certain
self-renewal
variation
H. A.
and
properties
cell
methods
cells
Buick,
examined
of the
the
blast
Leukemia
observed
progenitor
measured
culture
is
during
patient-to-patient
observed
patterns
remission
time
whether
stable.
REAT
R. N.
from
AML
patients
in culture.
Concentrations
of colonies
disease.
McCulloch,
in Acute
Toronto,
Ontario
Ontario,
M4X
Cancer
1 K9
Canada.
(
1 981
by Grune
& Stratton,
Inc.
0006-4971/81/5801-0015$OI.0O/O
105
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
106
McCULLOCH
Table
Patient
No.
Time of Study
Imo)
Leukocyte
Count
0
240,000
222,000
40,000
39,000
1
+ 6
3,000
23
7,200
35
36
3
8
of Clinical
Data
Absolute
Blast
Cell Count
+ 10
2
1 . Summary
Clinical
Newly diagnosed,
No response
0
Continued
before
to AAC,
relapse,
Status
When
Sample
Obtained
treatment
CAV
or MTX,
no response
1 .800
Relapse
after 2 remissions
1 3,000
6,000
Relapse
after
19,000
1 7,000
No response
26,000
18,000
In relapse;
partial
ET AL.
induced
remission
to further
VCR,
and 6-MP
or 6-TG
and
5-Azacytidine
with AAC
induced
ADR
no response
Pred,
to HU-ARA-C,
with
HU-ARA-C
+ ARA-C
to repeated
therapy
including
AAC
and
MTX,
Pred,
VCR
and
6-MP
9
20.000
1 3,000
No response
4
0
52.000
42.000
Newly
3
100,000
90.000
No response
5
11
22.000
20,000
Relapse;
12
27.000
25,000
No response
to AAC
1 3.5
2 1 .000
1 8,000
No response
to further
20,000
Newly
6
0
105,000
16
2,500
0
33,000
7
12
approved
by
the
0
70
900
Human
Studies
Committee
of
second
University
of
partial
treatment
remission
induced
complete
Blast
Assay
progenitors
method
described
peripheral
of
density
by
g/ml,
red
calf
These
progenitors
5%
CO2.
by
same
were
their
using
(Table
The
by
prepared
from
the
These
colonies
are
expressed
secondary
linearity
quoted
not
identified
by
1-4
containing
their
at
blast
then
with
and
SRBC.
by
In some
as determined
PE2
plates.
ogy
cellular
PE2
cultures
an
per
both
is independent
from
cell
the
to primary
0 to
were
incubated
>700.22
blast
growth
for 5-7
microscope.
The
referred
of some
available,
number
similar
20
of I 0 or 2 x I 0
drug,
value
(>5
by the
levels
has
dose
for
formation
required
D10).
from
very
to
plated
is
exponential.
(Adria
varied
10 mm
and
in colony
negative
measured
for
twice,
decrease
ofcontrol
was
exposed
washed
is characterized
to 10%
D10 Adria
are
This
to reduce
For
52 AML
sensitive
(<0.1
zg/ml).
Arabinoside
tors
of
using
were
cultured
formation
curve
exponential
(Fig.
a tail
resistant
the
by
<
dose
formation
Simple
required
in
number
l07M)
to resistant
most
negative
sensitivity
D10
>
the
by a simple
to
indicating
are
10%
from
dose-
negative
(approximately
observed
exponentials
survival
decrease
instances,
was
has varied
(Ara
was
progeni-
of increasing
of instances
curve
to reduce
Ara
presence
be approximated
1). In a small
patients
in the
observed;
could
arabinoside
et al.17 Blast
A dose-dependent
in the dose-response
population.
cytosine
by Niho
arabinoside.
was
obtained
to
described
of cytosine
colony
I 0%),
progenitors
method
for colony
concentrations
in
blast
the
(Ara
very
a
characterized
D10).
For
sensitive
42
(Ara-C
105M).
colonies
in colonial
colonies.’52’
D0
values
of negative
Packard
Computer
writing
ofD,0
for Adria
exponential
hand-held
Centre.
programs
Values
and
Ara-C
curves
were
determined
determined
using
or
University
calculator
The authors
are
for both computers.
the
the
grateful
to Dr.
from
the
either
of
Larry
slopes
a Hewlett
Toronto
Chang
for
RESULTS
from
values
Under
Computation
results
deviation
PE2
of
days
to as
concentrations.
are
were
of
methylcellulose,
a value
where
was
suspensions
excess
in
Because
of
colonies
composition
varied
cells,
number,
Secondary
Cell
in
inverted
l0
or PE2.
at
self-renewal
at concentrations
using
cell
al.’5
microwells
efficiency
higher
et
containing
The
as colonies
to undergo
Buick
plated
in
enumerated
primary
and
of
dishes
PHA-LCM.
at the
44 patients,
cells
by a simple
to Cytosine
measured
response
nature
stains
rosettes
l0
x
atmosphere
by freezing
in 5% DMSO
and
repeated
measurements
of the
progenitors
method
were
plating
conditions
cell
volumes
and
and
to adriamycin
Blast
of the
curve
to resistant
AML
culture
in 0.1-mi
medium,
et al.’6
be described
formation
the
Sensitivity
progenitors
A dose-dependent
can
Sensitivity
of
2).
of blast
measured
cells
and 6-MP
of Self-Renewal
capacity
colonies.
formation.
that
Sensitivity
D0
Measurement
VCR
AAC
of blast
dose-response
(PHAdetection
in a moist
and
preserved
permitted
and
the
Wright-Giemsa
to form
incapacity
medium),
were
days
Pred,
with AAC
concentration
zg/ml)
MTX,
of phytohemagglu-
these
Cultures
with
by Buick
patients,
leukocytes,
with
ofAdriamycin
sensitivity
colony
formation
hemochromatosis
enumerated
blast cells were
at - 70#{176}C.This
sample
when
a
6-MP
methylcellulose
permitted
for 5-7
morphology
demonstrating
instances,
20% FCS
even
incubated
Colonies
confirmed
with
methods.
were
(growth
presence
procedures
in AML
cells
nucleated
a-MEM
in the
found
at
remaining
in 0.8%
colony
by a second
rosette
plated
a patient
morphological
routine
(FCS),
from
the
the
from
of
obtained
Ficoll-Hypaque
The
were
preparative
cells,
after
(SRBC).
serum
modification#{176}
of T lymphocytes
Hypaque
conditioned
leukocytes
1CM).
blast
Ficollcells
a
through
depleted
populations,
fetal
by
were
blood
blast
10% of a medium
tinin
centrifugation
through
sheep
20%
using
Mononuclear
blood
containing
with
assayed
et al.’4
I .077
centrifugation
with
were
and
with Ara-C
increasing
by Buick
VCR
with AAC
remission
remission
Pred,
induction
remission
as described
Progenitor
MTX.
with AAC
remission
The
HU-ARA-C
with
induced
Measurement
Toronto.
Blast
with
to AAC
complete
diagnosed;
Relapse;
the
to further
diagnosed;
Newly
treatment
no response
initial remission
Relapse;
25,000
to further
diagnosed.
are
these
in
the
morphol-
In a series
of
Seven
patients
were
studied
at intervals
of from
I to
16 mo. In 2 patients
studies
were
made
before
and
after
complete
remission;
in the remaining
5 patients
extensive
cytoreduction,
but
not
remission,
was
achieved.
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
HERITABLE
Fig.
NATURE
1.
response
blasts
with
Ara-C
curves
from
AMI
OF CLONAL
two
studied
107
CHARACTERISTICS
dosefor
AML
patients
repeat-
edly. (A) Patient
3. Table
2. (#{149})
First examination.
(A)
second
examination.
(B) Patient
1, Table 2. (#{149},
0) First bleed. (U) second
bleed.
(A)
third
bleed.
Closed
circles
are fresh
and open circles
cryopreserved cells throughout.
Aro
Repeated
measurements
on the
showed
much
less
variation
than
between
patients.
Figure
1 illustrates
figure
Ana-C
blasts
similar
contains
sensitivity
same
patient
that
observed
the point;
the
the data for repeated
measurements
on 2 patients.
Although
Ara
from
the two
dose-response
patients
curves
AML
patients;
in contrast,
seen when the same patient
For Adnia
D,0 and Ara
ranged
For these
observed
from
extremely
attributes,
in repeated
2.
44
similar
PE2 values
were
was assessed
repeatedly.
D,0, values
among
patients
sensitive
as for PE2,
measurements
patient.
In only two patients
might
indicate
progression.
in Table
among
to
little
were
changes
In patient
highly
resistant.
variation
on the
was
same
observed
that
2, both PE2 and
Adnia
D,0 were increased
in a final sample
taken just
before
death,
while
both
properties
had
remained
unchanged
over
the previous
year.
Patient
7 was
treated
with AAC
and entered
remission.
The Ara-C
survival
curves
at presentation
and relapse
after
12 mo
are shown
in Fig.
2; the data
indicate
that
blast
progenitors
in this
patient
may
have
become
less
sensitive
to Ara-C
in the interval,
although
the values
and
Adnia
D,0
were
similar
to those
seen
at
presentation.
DISCUSSION
of
D,0 of
varied
almost
tenfold,
were obtained
from each
at every examination.
All the available
culture
data
is given
For PE2,
values
varied
from
0 to >700
of PE2
C
The
major
conclusion
properties
of blast
ity
to adniamycin
properties
of the leukemic
Complete
remission
marked
of
this
cell renewal
or cytosine
was
cytoreduction
clone
seen
study
is
and blast
arabinoside
cell
in each
in 2 of the
occurred
in the
that
the
sensitivare stable
AML
patient.
7 patients
others:
and
there-
fore, repeated
quantitative
determinations
of the three
properties
provides
evidence
that populations
of blast
progenitors
emerging
during
clonal
reexpansion
expressed
present
in
phenotypic
characteristics
before
treatment.
It follows
these
properties
observed
patients
may reflect
heritable
such,
evaluation
of properties
primary
plating
efficiencies
latter
vary
with
time
similar
to those
that the variation
among
the
leukemic
clonal characteristics;
as
differs
from measuring
of progenitors,
since
the
in response
to physiologic
factors
or random
events
occurring
during
clonal
expansion.’#{176}
Such
stable
or slowly
evolving
characteristics
of
leukemic
clones
may
reflect
biologic
features
of
leukemia
in each
patient
that
may
affect
outcome.
Indeed,
self-renewal,
a property
that may be related
to
clonal
tively
aggression,
correlated
was found
to be significantly
with
successful
remission
negainduc-
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
108
ET AL.
MCCULLOCH
Table
2.
Sum mary
of Laboratory
Data
Drug
Self
.
Timet
(mo)
Patient
0
+6
+10
2
6.8±1.9xlcY7
1
20
1
25
1
2.7
1
53
54
±
13
±
4
1
3.0
-
-
-
1
2.6
-
-
2
-
1
5
-
-
1
4.3
1
1.4
x
1
3.2
1
1.8
x 108
31
±
1
5.8
36
15
5
27
±
18
-
-
1
3.2
x
1O6
±
2.8
2
47
±
22
-
-
1
7.0
x
1O6
+ 1
2
93
±
4.2
2
92
±
4.9
-
-
1
3.2
x
1O
+2
2
56
±
4.2
2
75
±
5.6
5
1
4.3
x
106
6
.75
±
.74
5
3.5
±
2.9
0
+12
first
0
1
2
22±11
2
38
in Table
1
-
1
used
(0 time)
-
-
1
designation
3.3
30±5
1
5
1
38
-
-
-
-
-
-
-
-
-
-
1
2.2
1
3.3
SeeFig.2
1.
observation.
Secondary
plating
efficiency
determined
from
4 dishes
plated
with
1 O cells,
§Secondary
plating
efficiency
determined
from
4 diSheS
plated
with
2 x 1O cells. expressed
As yet,
1O6
±
-
iO
iO
16
7
tion.’522
x
x
28
0
any of the three
AML
(McCulloch,
8.1
1.6
-
3
31
±
3
-
7.2
124±30
1
+16
the
6.8
3
±
5
6
patient
2
1.7
3
0
after
2.1
1
13
2
5
Same
1
76±36
2
+4
tTime
55
5
+13
0
D0 Ara
(Molarity)
2
1
4
n
54±34
±
38
n
31
3
0
PE2 (2 x 1O)
5
0
+1
n
Die Adria
(ig/ml)
4
+ 12
3
Sensitivity
.
PE2 (1O)
n
1
Renewal
no correlation
has
attributes
Curtis,
and
and
been
found
expressed
as colonies/
1 O.
as colonies/
1 O.
between
other
risk factors
Messnen,
manuscript
in
in preparation).
Evidence
of developing
drug
resistance
observed
in only two of the seven patients.
This
was
finding
was unexpected,
since the development
of drug
resistance is observed
commonly
in experimental
systems.23
However,
the time of observation
in the present
series
was short;
a longer
time might
be required
to observe
clonal
evolution.
In the absence
ofsuch
observations,
it
would be inappropriate
we have
studied
are
seems
more
reasonable
to conclude
that the properties
invariant
with
time;
rather,
it
to consider
that
they
may
change
slowly.
It may be that the short natural
history
of AML,
together
with treatment
policies
that include
maintenance
therapy,
reduce
the probability
of the
emergence
of resistant
populations.
We believe
that
this is the first report
of stable
cellular
measured
characteristics
in short-term
association
outcome
between
of treatment
in
cell
heritable
provide
human
culture.
leukemia
The findings
characteristics
evidence
for
individualize
treatment.
Perhaps
any model
of AML
must explain
marked
and stable
patient-to-patient
,
‘
as
of
and the
a need to
of equal
importance,
the generation
of this
variation.
Ara-C
(Molority)
ACKNOWLEDGMENT
Fig.
The
technical
authors
assistance.
are
grateful
to
Alexandra
Cremona
for
excellent
patient
1 2-mo
2.
Ara-C
dose-response
curves
7. Table
1 . (A) At presentation.
remission.
for
AMI
blasts
(#{149})
at relapse
from
after
a
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
HERITABLE
NATURE
OF
CLONAL
CHARACTERISTICS
109
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From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
1981 58: 105-109
The heritable nature of clonal characteristics in acute myeloblastic
leukemia
EA McCulloch, RN Buick, JE Curtis, HA Messner and JS Senn
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