From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
Impaired
Pentose
Decreased
Chronic
Lymphocytic
By
T
I.
JEROME
inappropriate
BRODY,
Metabolic
A.
FRANK
OSKI
AND
that
leukemic
lymphocyte
glycogen,
defect.
suggested
It
was
soluble,
an
reasoned
( HMP)
shunt
accumulation
cogen
synthesis
The
when
associated
purpose
alterations
provide
more
a block
material
the
with
tolerance,
an
alternative,
that
intracytoplasmic
glucose
E.
DANIEL
.
..?
SINGER
in
storage
is related
to
UDPG
in the
glucosyltransferase,4
synthesis
or catabolism
dynamic
either
intracellular
the
hexose
metabolic
monophosphate
or the Embden-Meyerhof
( E-M ) pathways
might
lead
to an
of glycolytic
intermediates
which
could
ultimately
enter
the glycycle
and become
manifest
as increased
quantities
of diastase-
reagent.#{176} Similarly,
per cent of patients
gested
of
Pathway
glycogen
abnormalities
of enzymes
such
as phosphorylase,3
or a-D-glucosidase,5
which
are involved
either
of
and
in Lymphocytes
of chronic
lymphocytic
leukemia
contains
excess
glynumber
of patients
with
this blood
dyscrasia
have
and decreased
glucose
tolerance.2
The consistent
hyperglycemia
to demonstrate
Shunt
Activity
Leukemia.
HE LYMPHOCYTE
cogen’
and
a large
failure
Phosphate
Glycolytic
of
stainable
clinical
chronic
with
observation
lymphocytic
examined
under
inability
to
this investigation
utilize
in the different
glycolytic
a biochemical
explanation
for
the
periodic
made
in
leukemia
carefully
acid
controlled
carbohydrate
was
to determine
Schiff
this
laboratory
(CLL)
have
(PAS)
that
71
impaired
conditions,2
in a normal
whether
sug-
fashion.
proportional
pathways
of leukemic
lymphocytes
this cellular
and systemic
metabolic
might
ab-
normality.
METHODS
Lymphocyte
ies
MATERIALS
Donors
Patients
with
with
glucose-1-’4C.
and
AND
repeated
lymphocytic
chronic
Since
blood
the
withdrawal,
leukemia.
actual
Nine
experiments
practical
patients
provided
required
several
considerations
dictated
lymphocytes
visits
that
to
two
for
the
stud-
laboratory,
additional
pa-
From
the Department
of Medicine,
the Graduate
Hospital
of the University
of Pennsylvania,
the Department
of Pediatrics,
the Hospital
of the University
of Penn.sijlvania,
and the
University
of Pennsylvania
School
of Medicine,
Philadelphia,
Pa.
Supported
by research
grant
DRG-971
from
the Damon
Runyon
Memorial
Fund
for
Cancer
Research,
USPHS
training
grant
5T1 CA 5159 and USPHS
research
grants
CA07000
and HE-01919.
Presented,
in part, to the Xii Congress
of the international
Society
of Hematology,
New
York, N. 1., September
3, 1968.
First
submitted
November
4, 1968;
accepted
for publication
May
27, 1969.
JEROME
I. BRODY,
M.D.:
Associate
Professor
of Medicine;
recipient
of USPHS
Career
Development
Award
1K3-CA-8371.
FisNIC
A. OSKI, M.D.:
Associate
Professor
of Pediatrics;
recipient
of USPHS
Career
Development
Award
K-03-38600.
DANIEL
E. SINGER:
Work
done
as a summer
research
fellow.
Mr. Singer
is the recipient
of a Rhodes
Scholarship,
is now at Oxford
University,
and will ultimately
enter Harvard
Medical
School.
BLOOD,
VoL.
34,
No.
4
(OCTOBER)
1969
421
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422
BRODY,
Table
1.-Relevant
Clinical
Data
on Patients
with
Chronic
OSKI,
Lymphocytic
SINGER
Leukemia
Therapy
Patient#{176}
Number
Age
Sex
Diagnosis
Year
WBC+
(mm3)
1
64
M
1965
420,000
2
3
4
60
F
1958
57
F
1958
83
65
62
76
M
M
M
M
8
60
F
9
10
11
74
88
73
M
M
1967
1962
1968
1968
1968
1966
1968
1946
5
6
7
M
Lymphocytes
a
from
f All patients
marrow
had
Severe
52,300
assays,
peripheral
Chlorambucil
None
None
None
None
None
None
None
None
( see text).
smear
and
bone
36-39
cent.
lymphocytosis.
Severe:
hematocrit
23
per
cent;
mild:
Coombs
test negative
in each instance.
§ As methyl-bis-13-chloroethylamine
f Known
to have
diabetes
mellitus.
and Their
Components
Lymphocytes.
hematocnts
hydrochloride
tients
supply
lymphocytes
particularly
for
data are summarized
in Table
1.
Normal
controls.
Nine
healthy
hospital
lymphocytes
for assays with glucose-1-14C
for tests with
glucose-6-14C.
Assay
None
Chiorambucil
None
External
x-irradiation
None
None
None
None
None
None
10 and 1 1 used for glucose-6-14C
90 per cent lymphocytes
in the
at least
None
None
None
Mild
None
None
None
None
Mild
Mild
None
60,400
Present
Prednisone,
HN2
External
x-irradiation
None
40,000
46,000
44,000
9,000
55,000
52,800
37,000
90,000
patients
Prior
Anemia*
assays
varied
between
per
(Mustargen).
with
glucose-6-14C.
staff members
and
and two other volunteers
Their
relevant
medical
students
provided
cells
clinical
donated
especially
Preparation
All lymphocytes
were harvested
from defibrinated
peripheral
blood
by differential
centrifugation
and dextran
sedimentation.7’8
After gently
washing
once with KrebsRinger-Henseleit
buffer,
approximately
10 lymphocytes
could usually
be obtained
from each
20 ml. of normal
venous
blood.
After
separation
of normal
lymphocytes
the
major
source
of impurity
was
red cells.
In this instance
contamination
usually
did not exceed
25 per cent
of the final lymphocyte
collection
and admixture
with polymor
phonuclear
leukocytes
did not
occur.
Leukemic
lymphocyte
separation
was
95 to 99 per cent
pure,
the remainder
1-5 per
cent of the cells being
erythrocytes,
and the total
number
of lymphocytes
obtained
was
dependent
on the donor’s
total leukocyte
count.
After washing,
all lymphocytes
were always
suspended
in a standard
volume
of 1 ml. Krebs
buffer
prior
to introduction
into the cxperimental
system.
Plasma.
Plasma,
in 3 ml. aliquots,
was dialyzed
against
two 1000 ml. changes
of isotonic
saline
for
16
hours
to
remove
endogenous
glucose.
At
the
end
of
this
period,
sugar
was
not detectable
by the glucose
oxidase
method.9
To insure
sterility,
plasma
was passed
through
a Swinney
filter
holding
a cellulose
acetate
disc
of 0.22
u porosity.
Krebs
buffer.
Krebs-Ringer-Henseleit
buffer was prepared according to standard
specifications and stored
as recommended.’#{176}
Radioactive
sugars.
Glucose-1-14C
and glucose-6-14C,
with specific
activities
listed by the
supplier of 1-5 mC/mM
and 2-10
mC/mM,
respectively,
were obtained
in aqueous
solution from New England
Nuclear Corporation, Boston, Mass.
Performance
With
of
glucose-1-14C.
Assays
The
ability
of lymphocytes
from
the
first
nine
patients
with
CLL
From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
IMPAIRED
PENTOSE
PHOSPHATE
(Table
1 ) to produce
suspended
in Krebs
paired
normal
identical
14CO,
buffer,
volunteer.0
manner
and glycolytic
intermediates
was tested
in triplicate
with cells
autologous
plasma,
and homologous
plasma
obtained
from
a
The
except
423
SHUNT
cells
that
from
the
this
and
other
corresponding
normal
leukemic
donors
plasma
were
assayed
became
the
in
an
homologous
substitute.
The general
method”
consisted
of adding
12.5 X 106 lymphocytes,f
in a volume
dependent on the total number
of cells harvested
from each source,
to 2.5 ml. buffer
or sugar-free
plasma
contained
in a 25 ml. Erlenmeyer
flask. Four pC of glucose-1-’4C
(total
sugar
182
g. ) were incorporated
into a test volume
which
never
was more
than 3.8 ml. Each
flask
was gassed
for 30 seconds
with a 5 per cent CO2-95
per cent air mixture
and sealed
with a
rubber-sleeve
stopper
into which
was inserted
a plastic
ladle
holding
0.3 ml. of 0.5N
NaOH.
The mixture
was placed
in a Dubnoff
shaker
and incubated
at 37 C. for 3 hours
at
64 oscillations/minute.
At the end of this period,
0.5 ml. of 0.5 N perchloric
acid was
added
to the body of the flask by hypodermic
needle
through
the rubber
stopper
to release
‘4Co9.
The
gas
generated,
representing
sugar
metabolized
largely
through
the
HMP
shunt,t
was absorbed
by the NaOH
in the plastic
ladle during
the next 30 minutes.
The
stopper
was
removed
under
a fume
hood
and
the
ladle
rinsed
repeatedly
in
a scintillation
counting
vial containing
15 ml. Bray’s solution.14
The Erlenmeyer
flask contents
were centrifuged
for 10 minutes
at 2500 rpm. in an International
clinical
centrifuge.
The
clear
supematant
containing
collective
glycolytic
intermediates
was transferred
to a calibrated
test tube
and neutralized
with 2M KOH.
After
the resultant
total
volume
was recorded,
0.5 ml. was placed
on a 3 ml. Dowex
1 X 8
resin column
in the acetate
form which
had been washed
previously
with 20 ml. distilled
water.
The
carded.
resin
was
Glycolytic
collected.
The
from
and
and
again
in
which
this
retain
pyruvate
as
with
were
radioactivity
glucose
lactate
washed
intermediates
fraction
the
well
60
eluted
ml.
of
distilled
with
20
ml.
was
radioactivity
as
all
taken
of
of
the
the
water
With
glucose-6-14C.
production
as
a measure
position.
phosphorylated
HG
(total
(Table
sugar
plasma
Krebs
With
was
red
identical
were
control
as
on
Since,
potentially
To estimate
lymphocytes,
those
performed
a baseline
just
of
of
acid
eluate
of
represent
derived
mixed
in
X
leukemic
this
of erythrocyte
12.5
106
3.2
red
jiC
0.4
cycle to
10
it became
glucose
from
with
glucose-6-
patients
progressed,
influencing
medium
was
derived
thus
was
using
from
study
dis-
eluate
compounds
It would
described,
as the
capable
suspending
suspension
washings
intermediates
lymphocytes
the importance
a pure
the
all of this
the relative contribution of the Krebs
to
volunteers.
materials
used
cells.
assays,
jig.),
2 normal
contains
buffer
normal
‘4CO2,
182
1) and
that
In order to determine
of
and
HC1;
C-i
glucose-1-14C.
To prevent
color quenching,
0.5 ml. of the
ml. of iN NaOH
before counting in Bray’s solution.
the
iN
of
and
ii
apparent
utilization
only
assay.
contamination
cells
was
in the tests with
made
in
Krebs
buffer
with 4 jiG of glucose-1-14C and the assays repeated.
All samples were counted on a Packards Tri-Carh Scintillation spectrometer at a general
counting
efficiency
of 85 per cent in the range of radioactivity
employed.
Background
counts
were
insignificant
compared
to
those
of
the
sample.
RESULTS
The
ing
results
of
the
total
that
#{176}Plasmas were
the
‘4CO2
assays
contribution
not
using
of
necessarily
blood
the
glucose-1-14C
pentose
type
compatible.
assays,
did not influence
lymphocyte
metabolism
under
lined.
f A number
known
to avoid
a crowding
effect.’2’13
Some
C-i
‘4CO2
position
§ The
prior
Packard
may
be
entry
Instrument
to
evolved
in
the
from
citric
Company,
pyruvate
acid
Downers
are
phosphate
which
Isoagglutinins,
the
experimental
had
retained
cycle.
Grove,
reported
shunt
Illinois.
fully
to
realiz-
glucose
after
me-
several
trial
conditions
radioactivity
out-
in
the
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424
BRODY,
Table
2.-Metabolism
As mMoles
Krehs
of Glucose-i-’4C
Glucose/12.5
Buffer
by Leukemic
X
Autologous
Plasma
SINGER
Lymphocytes
Cells/3
106
08K!,
Hours
Homologous
Plasmat
#
Patient
No.
C.!.#{176} Total
1CO2
1
2
3
4
5
6
7
8
9
Mean
SE.
a
In
%Shf
14C
CI.
Total
%5h
%5h
11.3
5.0
5.1
94.3
63.9
41.7
105.6
68.9
46.8
10.7
7.3
10.9
1
2
3
47.1
59.9
50.4
2.9
2.5
4.8
3.0
1.1
4.1
51.4
17.2
40.9
54.4
18.3
45.0
3.5
75.3
78.8
4.4
8.1
54.7
62.8
12.9
8.9
53.4
62.3
14.3
4
2.1
2.4
1.3
2.8
1.3
48.1
40.9
24.7
38.0
30.5
50.2
43.3
26.0
40.9
31.8
4.2
5.5
5.0
6.7
4.1
.38
3.7
0.7
6.9
2.6
12.4
60.5
15.2
56.6
63.1
13.2
64.2
15.9
63.5
65.7
2.9
5.8
4.4
10.9
3.9
1.1
3.2
2.3
7.5
6.4
14.8
64.1
19.5
81.5
43.9
15.9
67.6
21.8
89.0
50.3
6.9
4.7
10.6
8.4
12.7
5
6
7
8
9
2.1
.26
45.5
5.0
47.5
5.2
4.5
.43
3.4
0.9
41.3
6.9
44.8
7.7
6.8
1.1
5.6
1.1
53.0
8.8
58.7
9.6
9fi
1.0
study,
this
Table
fraction
denotes
3.-Metabolism
As mMoles
Krebs
collective
glycolytic
A utologous
intermediates
from
donor
of Glucose-1-14C
Glucose/12.5
X
Buffer
the
listed
by
106
such
in Table
Normal
Cells/3
Plasma
enterring
HMP,
the
E-M
as 6-phospho-
3.
Lymphocytes
Hours
Homologous
Plasma
S
14CO
G.I.#{176}
Total
1
2
3
4
5
6
7
8
9
12.7
8.1
10.9
15.4
7.9
13.7
109.1
79.2
76.4
63.0
70.1
84.3
121.8
87.3
87.3
78.4
78.0
98.0
Mean
SE.
a
Total
45.7
58.4
48.0
pathway.
It is realized,
however,
that
intermediates
gluconate,
also may be present
in small amounts.
t Denotes proportion
metabolized
by HMP.
Symbol
# denotes
corresponding
normal
plasma
Normal
No.
G.I.
1.4
1.5
2.4
this
5.5
6.0
9.1
‘4COs
10.4
9.3
12.5
19.6
10.1
13.9
idGos
C.!.
17.8
12.3
22.4
14.0
30.8
20.5
108.4
97.9
140.7
82.8
195.6
143.4
Total
%Sh
14CO
G.I.
126.2
110.2
163.1
96.8
226.4
163.9
14.1
11.2
13.7
14.5
13.6
12.5
17.5
11.0
16.3
25.8
16.8
20.8
126.4
130.1
177.5
64.9
100.1
160.5
Total
%Sh
143.9
141.1
193.8
90.7
116.9
181.3
12.2
7.8
8.4
28.4
14.4
11.5
8.5
82.0
90.5
9.4
27.1
94.1
121.2
22.4
28.1
89.6
117.7
23.9
5.4
6.4
72.1
57.3
77.5
63.7
7.0
10.0
23.9
19.9
174.9
129.5
198.8
149.4
12.0
13.3
15.6
25.3
147.7
103.4
163.3
128.7
9.6
19.7
9.9
77.0
86.9
11.4
20.9
129.7
150.6
14.1
19.7
122
141.9
15.1
1.2
As
%5hf
4.9
5.4
in Table
1.2
1.9
19.1
14.1
1.1
1.9
12.0
11.0
1
2
3
4
5
6
7
8
9
2.4
2.
I As
in Table
2.
Symbol
# denotes
tabolism
be
may
labelled
glucose,
and transketolase
pathways.15
sumption
methodology,
on
corresponding
underestimated
intracellular
systems,17
Furthermore,
have
been
the
leukemic
because
donor
since
previous
estimates
divergent,12”9’20
values
are
presented
less
than those
lymphocytes
by normal
utilized
in Table
be
leukemic
lymphocytes
cells in the same
absolutely
(P <
glucose
multiple
should
con-
variables
considered
in
solely
cell.
medium
.0005
of the
transaldolase
phosphate
of lymphocyte
and
2.
rearrangements
via active
of nontriose
implying
a basis
which
compares
the normal
with
the
All aspects
of glucose
metabolism
by leukemic
appreciably
3) . Leukemic
listed
of molecular
metabolic
recycling15’16
and the potential
presence
widely
present
plasma
)
in buffer
were
( Tables
2 and
and
proportion-
From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
PENTOSE
IMPAIRED
ately
(P
their
normal
<
PHOSPHATE
.0005)
less
shunt
the
cent
11 to 22 per
collective
glycolytic
and
sugar
total
comparative
all
When
the
leukemic
glycolysis
mediates
the buffer
and the
values,
2
)
normal
in
<
.0005),
(P
<
all
facets
and
solute
Normal
(P
raise
bore
any
clinical
plasma
proportional
never
activity
of the
consistent
lymphocytes
in
leukemic
plasmas
tamination
of
values
of
Since
this
total
lymphocyte
consumed,
was
very
to
the
only
inin
for
level
leukemic
(Tables
2
lymphocytes
of
lyrnphocytosis,
plasma,
leukemic
sugar
metabolism
inhibitory
influence
of
Red
0.7
cell
m/Amoles
cell
ratio
in the
considered
ab-
consumption.
which
could
lymphocytes.
contributed
not
plasma
metabolism
sugar
media
a lymphocyte-red
it was
<
significant
degree
relative
assays
using
(P
cell
As with
normal
positive
effect
on
the
total
sugar
.0005).
.0005),
to a normal
leukemic
small,
response
glycolysis
<
.0005)
HMP
a suspending
statisti-
oxidative
HMP
was
duration,
autologous
normal
quantity
disease
are
to
7
incubations,
homologous
for
inter-
metabolic
with
cell
administered.
pronounced,
glucose
normal
described
contrast
on
(P
compared
neoplastic
to
therapy
but less
the
<
features
relationship
through
(P
provided
glycolytic
however,
absolute
increment
undergoing
cell-plasma
of
this
of the
metabolic
condition,
or
had a similar,
normal
same
but
sugar-free,
sugar
of
of assays,
in
as
are
depressed,
compared
from
patients
5 and
intermediates
utilization
.0005)
The
dialyzed,
increased
utilized
<
used.
quantity
terms
(P
of experiments
of
leukemic
lymphocytes
glucose
in
to
of
decreased.
freedom
slightly
plasmas
group
in
cent
plasma,
metabolic
mean
with
glycolytic
per
leukemic
of
autologous
None
this
plasma
of
and
,
of
markedly
own
< .025)
and
plasma,
however,
the
3).
and
their
.0005)
the
buffer
for
group
proportion
were
with
compared
production
Suspending
creased
The
demonstrated
suspended
utilized
values
this
hexose
quantities
cells
markedly
suspended
and
The
neoplastic
also
3 for
were
consumed
to results
contrast,
the
than
the
corresponds
study.21
degrees
amount
augmented.
of the
In
by
the
of
lymphocytes
were
2 and
with
sugar
mainly
lymphocytes
when
of
was
None
.
in Tables
shunt
utilization
normal
)
.0005
<
absolute
total
due
significant.
by
produced
(J
monophosphate
in an analogous
lymphocytes
the
hexose
proportional
cent
significant
plasma
( Table
per
intermediates
shown
the
mean
reported
consumed*
oxidative
(P
of 11.4
statistically
autologous
via
The
range
values
highly
cally
glucose-1-14C
counterparts.
monophosphate
425
SHUNT
to
of
final
the
conthe
3 to
1.
calcula-
tions.
The data
cant findings
10.1/1
glucose
for the glucose-6-14C
assays
are a glucose-1-14C/glucose-6-14C
to 7.5/1
utilization
to assays
observations,
in
a The
other
and
phrase
of
summarized
laboratories,21’22
indicate
that
“total sugar
glucose
and
consumed”,
produced
the
by
in Table
production
4. The signifimean
ratio of
respectively,
proportions
are
and a total
comparable
14c02
in normal
and leukemic
lymphocytes,
ratio
very close
to unity.
These
generation
of 14co2 by normal
lower
glucose-1-14C/glucose-6-’4C
derivatives
are
help
support
the validity
Krebs
cycle
contributes
leukemic
lymphocytes.
ratios
developed
by
as used
lymphocytes
in this
the
investigation,
detectable
by
of
the present
minimally
to
The cause
for
leukemic
cells
denotes
the
methods
the
oh-
all metabolic
described.
From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
426
BRODY,
Table
4.-Comparative
Metabolism
of Glucose-i-14C
and Glucose-6-14C
Glucose/12.5
X 106 Cells/3
Hours)
Buffer
Donor
A
B
10
11
G.I.
11.2
9.0
§
%#{176}
“CO
12.1
9.9
.9
2.9
60.3
63.2
4.6
.4
61.4
61.8
3.1
57.0
60.1
5.2
.4
64.4
64.4
as
1.1
Ratios
Total%
CI.
92.3
90.3
1-’CO2
T-1-’C
6hlCOs
T-6-”C
69.4
70.5
1.7
10.2/1
78.8
79.7
1.1
10.0/1
1.3
1.1
.65
7.2/1
1.0
.62
7.8/1
.93
‘COO.
I T denotes
total
t Letters denote
§ Patients
10 and
tamed
would
Glucose-6-’4C
Total
81.1
81.3
Proportion
a
in Krebs
(mjzMoles
Glucose-1-14C
“COW.
SINGER
OSKI,
sugar
utilized.
normals.
11
listed
in Table
1.
from
the 2 patients
studied
be impertinent
to base any
remains
conclusion
undefined
on this
for the moment,
since
number
of determinations.
it
DiscussioN
The
significantly
diminished
quantities
of
by the leukemic
lymphocyte,
compared
that
this
neoplastic
cell metabolizes
HMP
pathway.
The
genesis
of this
moment
but
a number
of possible
the amount
of total
vivo may be limited
ment
when
glucose
inasmuch
glucose
utilization
the experiments
probably
observed
with
is the
clinically
CLL.2
In
by
were
laboratory
when
addition,
and 6-phosphogluconate
HMP
pathway,
are
the
leukemic
prevented
strate
lular
binding.2
control
normal
The
as
from
may
be
cells above
in suspending
mentioned
concentrations
the
oxidative
correct
restricts
and
spatial
may
renders
be
in
glycolytic
analogous
the CLL
facilitative
such
metabolism
on patients
as
glucose-6PD
govern
Finally,
enzymes
for
in
aug-
consumed
failure
most
large
measure
lymphocyte.23’24
orientation
First,
lymphocyte
significantly
carbohydrate
are performed
of enzymes
which
leukemic
briefly.
the quantities
buffer.
This
of impaired
tolerance
tests
certain
glucose-1-14C
the
in
may
optimimum
be
sub-
to the defective
intracellymphocyte
insensitive
ribosomal
assembly
to
in preparation
growth.2#{176}
via
yet
unproven,
several
If, for
glycolytic
example,
pounds
it could,
glucose-i-phosphate
ferase
upon
expression
glucose
This
abnormality
mechanism
which
observation
utilization
the leukemic
performed
the
and
evolved
actually
available
to the leukemic
as leukemic
plasmas
did not
undergoing
stimuli
mechanisms
dehydrogenase,
diminished
in
lymphocyte,
from
proliferative
for
oral
14co2
with
its normal
relative,
is evidence
proportionately
less sugar
through
the
deficiency
remains
speculative
for the
(glycogen
the levels
the
that
leukemic
HMP
shunt
idea
that
these
intermediates
glucose-6-phosphate
through
for
lymphocytes
cells
which
concentrations
with
contain
the
excessive
ultimately
were
one
phosphoglucomutase,
glycogen
synthesis.
synthetase)
of glucose-6-P.27
demonstrate
is compatible
in glucose
proposed,
quantities
of
but
one
or
result
in cellular
glycogenesis.
of these
phosphorylated
corn-
provide
Relevantly,
have
a defect
initially
been
increased
UDPG
shown
amounts
glycosyltrans-
to be
dependent
of
From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
iMPAIRED
PENTOSE
The
final
PHOSPHATE
point
out
disorders
lymphocyte
glycogen
storage
and pathis time.
It is pertinent,
nevertheless,
to
that patients
with
classic
diabetes
mellitus
and lymphoproliferative
are both
prone
to the same
forms
of bacterial,
mycotic,
and granu-
lomatous
infections,
tient
clinical
427
SHUNT
effects
hyperglycemia
of
remain
leukemic
moot
and
that
at
a new
British
immunosuppressive,
appears
to act by inhibiting
mitochondrial
and by interfering
with
the utilization
It is conceivable
that the restricted
abilities
depends,
in some
47,776,
phosphorylation
and generation
of
of ATP
produced
by glycolysis.28
of the leukemic
lymphocyte
in im-
ATP,
munogenesis29’3#{176}
I.C.I.
manner,
on
its
metabolic
disturbance.
SUMMARY
The
purpose
the
hexose
in
mic
of this
study
monophosphate
lymphocyte
glycogen
cause
for
with
lymphocytic
of
buffer,
spectrometry.
Compared
consumed
less
via
minished
quantity
significantly
sugar
hexose
of
plasma
certain
became
the
normal
but
lymphocytes,
also
for
failed
instances,
14co2.
all facets
to stimulate
this
of
plasma
along
with
similarly
handled
except
that
as
depressed
intermediates,
scintillation
cells
not only
less
indicated
autologous
lymphocyte
lymphocytes
Evolved
by
proportionately
Although
further
substitute.
pathway
normal
leukemic
Krebs-bicarhonate
plasma,
collective
glycolytic
were
assayed
the leukemic
shunt
generated
in
excess
a possible
of patients
technic
con-
normal
homologous
metabolized
monophosphate
increased
leukemic
were
hydroxide,
and
chromatography,
to
total
the
lymphocytes
plasma
sodium
exchange
separately
homologous
alterations
of leuke-
explanation
.
paired
control
leukemic
trapped
by
by anion
drate
a biochemical
in addition
to delineating
shown
by a large
number
( CLL) The experimental
lymphocytes
and
Normal,
corresponding
In
leukemic
autologous
glucose-i-’4C.
isolated
provide
leukemia
incubating
and
14C00,
might
glycolysis
proportional
pathways
stored
in these
neoplastic
cells
the decreased
glucose
tolerance
chronic
sisted
was to determine
whether
shunt
or Embden-Meyerhof
carbohyby
the
normal
di-
plasma
glycolysis,
autologous
in a similar
manner.
neoplastic
lymphocyte
glu-
cose
utilization.
These
observations
are consistent
with
the hypothesis
that
leukemic
lymphocyte
glycogenosis
may
be a consequence
of an augmented
pool of one or several
glycolytic
intermediates
ultimately
available
for glycogen
synthesis,
and
utilization
in many
with
leading
patients
the
to
with
idea
that
clinically
CLL.
leukemic
SUMMARIO
Le
in
Ic
objectivo
shunt
glvcolyse
excesso
causa
del
de
de
possibile
presente
studio
monophosphato
do
lymphocytos
pro
esseva
thesaurisate
Ic
reducite
numero
de patientes
con chronic
consisteva
in incubar
lymphocytos
Krebs e in autologe
e appareate
lymphocytos
de confrolo
esseva
leucemic
esseva
usate
como le
esseva
capturate
per hydroxydo
in
iste
tolerantia
in
vivo
carbohydrate
glucose
metabolism
INTERLINGUA
determinar
hexosa
provide
restricts
abnormal
IN
de
leucemic
glycogeno
plasma
detected
o
si alterationes
in
Ic
possihilemente
cellulas
pro
de
un
neoplastic
glucosa
proportional
circuito
explication
insimul
que
es
occurrente
Embden-Meyerhof
con
manifestate
Ic
del
biochimic
pro
indication
de
per
un
Ic
tin
grande
leucemia
lymphocytic
(CLL).
Le technica
experimental
leucemic
separatemente
in tampon
a bicarbonato
de
homologe
plasma
normal
insimul
con glucosa-i-14C.
Normal
tractate
similemente,
excepte
que un correspondente
plasma
substituto
homologe.
Le ‘4CO2
que se disveloppava
e (iie
de natrium
e collective
intermediatos
glycolytic
isolate
per
From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
428
BRODY,
chromatographia
Comparate
con
a excambio
lymphocytos
sucro
etiam
total
sed
anionic
normal,
esseva
essayate
per spectrometria
le cellulas
leucemic
non solmente
metabolisava
proportionalrnente
circuito
generate.
metros
shunt
de monophosphato
de hexosa,
Ben que autologe
plasma
normal
del normal
glycolyse
lymphocytic,
lymphocytos
leucemic
in un simile maniera.
ditionalmente
le utiuisation
del
glucosa
minus
hydrato
OSKI,
SINGER
de scintillation.
consumeva
minus
de
carbon
via
Ic
indicate
per le reducite
quantitate
del 14C02
augmentava
significativemente
omne
le paraautologe
plasma
leucemic
non
stimulava
Ic
In certe
casos,
iste plasma
deprimeva
ad-
ab lymphocytos
neoplastic.
Iste
observations
es de
accordo
con le hypothese
que le glycogenese
de lymphocytos
leucemic
es un consequentia
de un auginentate
pool
de un o plure
intermediatos
glycolytic
que
es ultimemente
disponibile
pro le synthese
de glycogeno
e con le idea que plasma
leucemic
restringe
in
vivo Ic utilisation
de glucosa
e resulta
assi in le clinicamente
detegibile
anormalitate
dcl
metabolismo
de hydrato
de carbon
in numerose
patientes
con CLL.
ACKNOWLEDGMENT
Able
technical
assistance
was
provided
by
Mrs.
Mary
Haidar.
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1969 34: 421-429
Impaired Pentose Phosphate Shunt and Decreased Glycolytic Activity in
Lymphocytes of Chronic Lymphocytic Leukemia. Metabolic Pathway . . . ?
JEROME I. BRODY, FRANK A. OSKI and DANIEL E. SINGER
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