From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
Nucleic
By FELICE
Acids
and Protein
in Acute
Leukemia
GAvosro,
CIOvANNI
I
MABAINI
T IS generally
agreed
that
the
specific
sequence
of
from
DNA
( desoxyribosenucleic
the genetic
the amino
acid
RNA.1
important
On
the
basis
forts
have
been
and
RNA
of
made
tory
during
the
cells.
elution
past
years
on
profiles,#{176}1
have
nucleic
to
the
acids,
detect
weight
ef-
in the
DNA
composition,’M,9
and
and
of
considerable
base
unspecific
defines
transmitted
sequence
is
Peculiarities
content,27
molecular
yielded
which
in the cell
protein
chains
the
nucleotide
acids
of
through
of
PILERI
other
physico-
sometimes
contradic-
results.
tion
dynamic
information
of isotopically
corporation
has
chronic
been
leukemia.
More
reliable
compounds
olism
been
and
useful
and
leukemic
technic,
RNA
and
dine2
The
and
and
present
autographic
in
protein
deals
in
the
on
were
investigated.
has
with
to
(s.a.
leukemic
tritium
study
I)NA,
RNA
as
well
study
of
RNA
be
easily
incubation
could
Bone
as
containing
marrow
was
Medical
May
20,
of
this
technic,
and
in
types
labelled
DNA
precursor,
of cellular
ohtained.1924
been
cellular
tritium
metab-
H3-thymi-
proliferation,
With
the
studied
utilizing
both
same
H3-cyti-
protein
in
tlmis
tritium
by
obtained
their
blast
precursors
8 patieimts
phase
purpose
of
Since
FI:I_thyimiidine
was
tmncline.
puncture
of
University
1960;
accepted
for
publication
1555
Cells
(fig.
sternal
of the
uridine
synthesis
labelling
Clinic
RNA
A radio-
employed.
untreated
in
acute
( s.a.
H:u_uridine
l)NA
labelled
DNA.
cells.
was
witim
mmmc. mrmNl ),
nmetabolismmi,
time
of
normal
II3-DL--phenylaIanine
heavy
by
investigation
METHODS
of
890
an(l
not
For
recognized
AND
and
( s.a.
and
cells
metabolism.
value
same
DNA
also
labelled
donors
mc.’mNI)
RNA
DNA,
mixture
From
the
Torino,
Italy.
Submitted
6 normal
29.1
of matura-
intrinsic
with
With
a comparative
acute
H3-thymidine
H3-DL-leucine
the
specific
kinetics
has been
marrows,
utilizing
of
stages
as precursors
report
marrows
bone
comparing
regard.
MATERIALS
Time
fri-
pleomorphism
at various
decreases
the
most
metabolism
metabolism
technic
of
lymphocytes
cellular
types
by
this
information
bone
degree
in the
Autoradiography
the
utilizing
H:s_DL_leimcine2a
protein
obtained
tool
except
extreme
incorpora-
tIme
methods.
marrows.
useful
very
in normal
be
bone
studied
the
marrows
chemical
studying
a high
cells
of cellular
bone
may
leukemic
is a very
has
dine,
data
and
by
precursors:
However,
leukemic
by
obtained
acid
in all leukemic
percentages
obtained
in normal
been
nucleic
detected
lymphatic
results
these
has
labelled
resulting
in different
tion in normal
and
used
information
)
ALESSANDRO
AND
role
Studies
characteristics1314
More
of
this
leukemic
chromatographic
chemical
of
Metabolism
Cells
(s.t.
126
will
be
nmust
added
time
phase
were
incorporated
selected
the
of
into
for
sample
I)NA
of
synthesis
1 a & Fm).
and
Torino
Aug.
aspirated
(Prof.
8,
G.
1960.
into
a
C. Dogliotti,
),
mmmc./mM
mmmc. mM)
be
to
leukemia
62
heparinized
Director),
the
the
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
1556
GAvOSTO,
MARAINI
AND
after H3-Uridine
incorporation
in acute
No. 7 has incorporated
also H3-Thymidine:
that detected
in the other cells.
leukemia
its
PILflI
a
Fig. 1.-Nuclear
labelling
(cells
1,2,3,4,5,6).
The cell
of labelling
is about
sevenfold
syringe.
It
Medium
and
concentration
to
of
2.5
of
diluted
into
sc./ml.
10
with
siliconized
and
p.c./ml.
test
after
Incubation
made
on gelatine-coated
1, 2 and 3 hours
for uridine,
autoradiographic
10
Kodak
plates.
(;iemmmsim
method.
The
grains
the
cells
volume
and
were
made
the
smmiears
Eagle’s
was
Basal
then
one
out
in
hour
plmenyialanine.
counted
by
were
time
stained
amid
system
incubation
After
usual
time
fixation
grain
a final
added
at
for
stripping
by
to
were
a rotating
of
Essential
added
H3-DL-$-phenylalanine
carried
after
were
of
H3-thymidine
was
ieucine
processing,
over
equal
and
slides
preparations
After
an
tubes.
H3-DL-leucirme
were
solution,
AR
immediately
transferred
a concentration
Smears
and
was
cells
degree
37
thyrnidine
in
Carnoy’s
technic,
the
count
using
May-Griinwaldof
the
back-
C.
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
NUCLEIC
ACIDS
ground
was
40 myeloblasts
AND
PROTEIN
subtracted.
in each
METABOLISM
The
degree
normal
bone
IN
of
isotope
1557
LEUKEMIA
incorporation
marrow
and
in
was
estimated
from
cells
200
at least
of acute
in
each
case
leukemia.
In
normal
one
contmntmed
and
after
resimspended
one
in
cubation
was
a
one
hour,
acute
leukemia
the cells were
medium
continued
containing
for seven
marrow,
incubation
washed
three
imnlabeiled
with
with
times
imridimme (2
Hauridine
was
Eagle’s
dis-
Mediunm
and
which
after
mmmM/ml.),
in-
hours.
RESULTS
Thymidine
evident
other
tritiated
in acute
hand,
ent
in normal
values
and
cells
for
mean
table
in
incorporation
1; these
was
almost
significant
data
Present
in
exclusively
all
in
differences
among
the
mean
not
is
On
significantly
grain
after
1)0th
nuclei.
the
which
myeloblasts.
were
obtained
cells,
the
cells
of labelling
the
differ-
cells.
for
were
normal
counts
blast
values
of
percentage
with
grain
labelled
percentage
lower
as compared
the
leukemic
the
A strikingly
Incorporation.-The
shown
curred
thymidine.
leukemia
the
Uridine
are
1 shows
lncorporation.-Table
incorporated
of
Uridine
incubation.
of
Ietmkemic,
and
did
analysis
the
for
hour
and
normal
Statistical
myeloblasts
counts
one
various
not
normal
oc-
reveal
bone
mar-
rows.
The
ly
uptake
and
(P
rows
detected
significantly
<
observed
0.001).
in
relationship
the
to the
in the
lower
cells
than
Striking
different
from
that
cases
in
differences
cases
different
of
cytologic
in
acute
Normal
bone
marrowmc
the
leukemia
from
degree
leukemia.
types
Table
Leucine
mean
grain
count/cell
of acute
myelohlasts
of acute
of
was
normal
uridine
These
constanthone
mar-
uptake
differences
were
bore
no
leukemia.
1
Ihenyl’itanine
mean
gran
count/cell
Ii rich ne
mean
grain
count/cell
Thymidine
,
labelled
cell,.
Case
1
49.4
±
34
:36.7
13
:33.9
15
50
Case
2
62.3
±
:33
49.5
±
25
52.8
34
53
Case
3
62.7
±
:37
40.6
±
13
Case
4
52.5
±
17
46.2
±
9
44.2
2()
-
Case
5
49.9
±
13
39.5
±
15
49.7
26
35
Case
6
57.3
±
18
41.9
10
38.9
12
35
54.4
±
2S
40.7
18
43.4
22
42
12.3
±
6.5
10.3
±
7.8
14.2
±
5
1.4 ±
1.7
±
2.5
5.0
Mean
vahmes#{176}
Acute
Leukemias
Stem
cell
leuk.
Micromyeloblastic
Myelobiastic
The
1.6 ± 1.8
1.7 ± 2.1
30.8 ± 19.7
40
±-
0.2
±
18.3
±
14.6
1.4
5.3
±
4.5
1.5
6.3
13.1
±
12
9.1
20.4
±
8.7
1
4.4 ± 5
25.8 ± 16.8
10.6 ± 8.2
values
for the mean
grain
counts
for
leucine,
phenylalanine
to the first hour of incubation
and to an exposure
of 20 days.
#{176}Statistical analysis
did not show significant
differences
between
different
normal
bone marrows.
1
6.4 ± 5.3
15.2
16.4
13.2 ± 13
and
the
uridine
myloblasts
1.5
6.6
4
are
referred
of
time
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
1558
GAVOSTO,
incubation
\Vhen
the
cytoplasm
cells
were
dine
the
the
same
washed
Amino
cine
hour
of
(hiring
icant
hours
differences
The
among
lower
(P
0.001)
<
shown
2),
the
of
in
in
a medium
PILERI
progressive
labelling
incubation,
the
containing
of
labelled
unlabelled
labelling
was
occurred.
f(r
1.
in
was
shown
still
This
mean
un-
present;
was
of
amino
acids
from
at
observed
to
cells,
in the
linearly
di(l
various
normal
lenfirst
nucleus
time
show
bone
and
leukemia
for
the
with
not
constantly
acute
to
both
aiiaiysis
of
refer
increase
was
counts
data
all the
the
cases
grain
These
Statistical
myelohlasts
cells
the
table
occurred
and
both
the
of
labelling
of incubation.
incorporation
hours,
hour
cytoplasmic
valimes
are
(fig.
7
AND
myeloblasts.
incorporation
three
one
nuclear
incorporation-The
cytoplasm
the
the
in leukemic
incubation;
5 to
in
in
in
phenylalamne
in the
and
and
for
after
resuspended
increase
a diminution
acid
and
When,
and
in normal
1)0th
evident.
progressive
time
prolonged
‘as
was
MARAINI
signif-
marrows.
significantly
than
normal
in
myeloblasts.
Table
2 shows
activity
about
of
six
the
values
precursors.
times
greater
two
amino
for
In
that
On
constant.
remarkably
of
the
the
acids
incorporation
normal
of
the
varied
corrected
myelohlasts
phenylalanine
the
for
the
and
uptake
this
other
hand,
the relative
greatly
in the different
ratio
leumcine
appears
degree
of
cases
specific
same
of
was
be
to
incorporation
of acute
leukemia.
DIScUSSION
In
acute
leukemia
thymidine,
evidence
normal
obtained
as
of
other
decrease
shown
a decreased
myeloblasts.
by
the
already
by
in
previous
proliferative
This
is
investigators27
in
the
percentage
capacity
good
utilizing
of
cells
investigations,23
of
agreement
the
these
with
has
cells
the
labelled
been
statmokinetic
method
S
.
2.-Leucine
incorporation
in
acute
leukemia
as
as compared
results
previously
3.
Fig.
with
taken
cells.
on
hone
to
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
NUCLEIC
ACIDS
AND
PROTEiN
METABOLiSM
IN LEUKEMIA
Table
___________
_______
Normal
bone
marrows
Case
mean
grain
count/cell
Case
1
2
Case
3
272
Case
4
228
Case
5
216
Case
6
248
Acute
214
270
2
Phenylalanine
mean
grain
count/cell
Leucine
-
1559
Uridine
mean
grain
count/cell
U/L
ratio
U/Ph
ratio
±
147
:36.7
±
13
67.8
±
:31
0.31
1.84
±
143
.195
±
25
105.6
±
68
0.38
2.13
±
176
40.6
±
±
7:3
16.2 ±
9
88.4
0.38
1.91
±
56
39.5
±
15
99.4
40
i 53
(1.45
2.5i
±
78
.119
±
10
77.8
21
0.31
1.85
.36.6
J: 29
0.81
1).6
±
(3.17
7.57
5.24
13
--
-
i
Leukenmias
Stein
cell
53.3
± 28
,,
,,
,,
44.7
±
34
,,
,,
,,
61.6
±
22
1.4 :± 1.1
,,
,,
,,
5.0
lemmk.
Nlicronmveloblastic
Nlyelohlastic
marrow
7.4 ±
11
6.9
±
8
7.4
±
9
133.0
values
The
are
counts
seem
to indicate
confirms
that
the
±
24
:3.55
17
5.87
10
1.73
33
0.22
12.8
±.
±
17
30.4
26.4
of
of DNA
26
-
2.90
1.17
2.49
--
activity.
significant
normal
a decreased
-
i
S
of
-
±
±
rate
interpretation
1)
5
specific
-
26.2
±
in
--
40.8
10.6
absence
cells
6.0
25.8
same
The
labelled
±
-
4.4
time
vitro.
in
of
the
for
--
--
85
corrected
cultures
grain
--
and
differences
leukemic
synthesis
in the
is essentially
mitotic
mean
myelohlasts
would
the
capacity
of
same;
acute
this
leukemia
cells.
Our
data
although
show
acute
cells.
RNA
acute
are
RNA
and
those
proteit
myeloblasts.
The
recent
investigations
ively
in
the
experiments
uridine
has
is
also
in
we
nucleus
to
phenomenon
cells
are
the
to be
well
a
compounds
far
at
or
even
the
compared
cellular
increased
with
normal
and
IINA
was
synthesized
cells
in
a later
incorporation
the
to
marrow
by
that
a
Investigations
determine
RNA
laboratory.
turnover
exclus-
cvtoplasm.28’9
and
nucleus
Since
medium
in
Our
leukemic)
and
The
same
Feinendegen
a decrease
real
constituent,
almost
(normal
the
period.
with
coincident
occurs.
in this
is
J-96)
cultured
in vitro.
resuspended
in unlabelled
assume
to
a cytoplasniic
it
exclusively
in
H3-cytidine
as
results:
these
of a decreased
transferred
bone
only
reasonably
in progress
in
so
as
mainly
that
incorporated
cytoplasm
as
now
human
labelling
may
cells
interpretation
appears
cells
(Osgood
the cells were
cytoplasmic
activity,
lower
of these
made
leukemia
precursors,
for
a normal
the
protein
significantly
turnover
demonstrated
subsequently
in
for
account
a lower
demonstrated
labelled
observed
leukemic
in which
an(l
and
cells.
RNA
initially
becomes
been
human
ments
that
RNA
investigations
acute
in
and
show
cytoplasm
only
to support
have
nucleus
may
or
which
protein
turnover
in these
Although
intracelhmlar
of
is constantly
possibilities
Thorell,7
seems
case,
content
content
This
incorporation
to
protein
cells.
of
the
case
Two
and
leukemia
level
that
from
leukemia
decreased
in
also
different
that
et
in
nuclear
of
RNA
designed
to
quantitate
normal
al.2
in
the experithe increase
transfer
in
the
phenomenon
and
radiofrom
the
this
leukemic
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
1560
GAvOSTO,
The
existence
was
OliSlTfl
RNA
of
is directly
fer
of
mechanism
of nuclear
of
synthetic
mammalian
it
of
that
altered
(table
be
ratio
in
acute
of an
considered
related
the
to its
cells
for
3).
From
and
cells
as
trans-
RNA
all
the
the
of
is the
specificity
in
resting
and
different
present
amino
the
demonstrated
case
acid
compared
we3
cellular
investigation
incorporation
with
defect
dissociation
is
normal
of
to
these
of
differentiate
seems
protein
inyelo-
to
RNA
related
and
to
of
proteins,
and
be
metabolism
finality
of specific
possibly
capacity,
and
metabolic
synthesis
could
elements
proliferative
RNA
a well-defined
(growth,
leukemia
these
between
of
The
etc.).
lower
functional
evidence
acute
of
their
the
in
the
been
the
in
holds
uridine
leukemia
Thus,
determines
has
(fig.
between
functions
specific
of
incapacity
with
metabolism
in
template
cells.
In normal
bone
marrow
of such
a strict
interrelationship
existence
interrelationship
as
differentiation,
in the
proteins.1
and
both
differentiating
of maturation
a
metal)-
Caspersson.
both
as
PILERI
2).
existence
tion,
Protein
specific
interrelationship
the
and
synthesis,
cytoplasm
AND
protein
Brachet
and
authors,3214
that
degrees
protein
of
the
This
and
and
is evident
The
to
several
growing
RNA
constantly
can
by
of
of
microsomes3”
synthesis
processes.
at various
blasts
the
the
auid
RNA
investigations
process
to
to demonstrate
between
types
in the
of
between
pioneer
information
tissues
in the case
were
able
the
aminoacids
carrier
the
interrelationship
by
involved
activated
intimate
a strict
eStil)liShe(I
MARAINI
protein
to
the
cell
metabolism
the
mature;
constitute
the
matura-
well
this,
most
known
together
important
elements.
SUMMARY
DNA,
RNA
resolution
by
and
protein
metabolism
autoradiographic
studying
the
technic
incorporation
A strikingly
phenylalanine.
in
of
lower
was
investigated
normal
and
tritiated
by
acute
thymidine,
percentage
of
uridine,
cells
labelled
#{149}peb
=
means
leukemia
of
a
blast
leucine
with
high
cells
and
thymidinc
.peb
#{149}mb
#{149}mb
E
#{149}pmc
#{149}oe
#{149}prnc
#{149}be
Lmc
Leucine
Lmc
mean
grain
couni>/ceu
Fig. 3.-Interrelationship
between
marrow
cells. PEB = proerythroblasts;
MC = myelocytes;
BE = basophilic
blasts;
L = lymphocytes.
Ptmeruylalanirie
mean grain coun/cefl
RNA and protein
metabolism
in normal
bone
MB = myeloblasts;
PMC
=
promyelocytes;
erythroblasts;
PE = polychromatic
erythro-
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
NUCLEIC
was
ACIDS
AND
PROTEIN
in
demonstrated
decreased
and
In
acute
proliferative
leucine
normal
was
and
leukemic
and
in
the
nucleus
during
only
The
in
in
constant
normal
The
the
first
later
ratio
of these
and
was
acid
metabolism
as
acido
investigate
per
blastocytos
normal
in
die
tritiate
thymidina,
basse
leucemia
procentage
acute,
capacitate
related
and
to
1)0th
fl
exclusively
the
cytoplasm
in
became
incorporation
leukemia
its
the
detected
cells.
dissociation
in acute
well-known
leucina,
leu-
maturation
defect
de
lo que
e
le
marcate
Ic incorporation
esseva
in
de uridina
e illo
de
esseva
de
Ie
fixation
leucemia
de
cytoplasma.
le
umn reducite
del
prime
amino-acidos
Uridina
hora
solmente
in
periodos
(letegite
in
myeloblastos
dIC
acute.
esseva
incubation,
del
subsequente.
normal
se monstrava
inter
invariabilemente
acute.
de
leucemia
maturation
le
durante
demonstrate
de
in cellulas
de amino-acido
de leucemia
metabolismo
cellulas
defecto
Ic marcation
esseva
indication
reduction
in
resolu-
frappantemente
le incorporation
etiam
in le nucleo
que
a alte
thymidina
detegite
proteina
Ic incorporation
Un
como
leucemic,
como
constante
in cellulas
reducite
con
significative
cellulas
acceptava
proportioii
alterate
muilto
e
determmante
e phenylalamna.
interpretate
nucleo
ribonucleic,
autoradiographic
acute,
esseva
in
acido
technica
cellulas
exciusivemente
e le cytoplasma
Le
un
leucina,
Un
in
1NTERLIN(UA
lemmceniia
uridina,
normal
tanto
incorporate
(Ic
e dc
e phenylalanina
cellulas
occurreva
iN
(lisoxyribontmcleic.
me(lio
Proliferative.
umridina,
tion
acid
amino
in acute
altered
protein
(Ic
tion
Le
and
a
of uridine,
occurred
incorporated
and
of
cells.
incorporation
incubation
uridine
always
discussed
metabolismo
esseva
In
uptake
leukemia
was
evidence
cells.
Lu
in
lower
acute
uridine
SUMMARIO
Plus
as
period.
was
RNA
cells
amino
of
interpreted
significantly
in
hour
between
myeloblasts
lower
kemia
a
cytoplasm;
was
detected
cells,
the
1561
LEUKEMIA
and
A very
capacity.
nucleus
IN
leukemia
phenylalanine
the
labelled
METABOLISM
acido
ribonucleic
acute
de iste
es
e de
discutite
in
proteina
relation
e su
al
dissocia-
ben-cognoscite
cellulas.
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1960 16: 1555-1563
Nucleic Acids and Protein Metabolism in Acute Leukemia Cells
FELICE GAVOSTO, GIOVANNI MARAINI and ALESSANDRO PILERI
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