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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 6 (March 15), 1998:
pp. 1845-1851
Evaluation by Multivariate Analysis of the Differentiation Inhibitory
Factor nm23 as a Prognostic Factor in Acute Myelogenous
Leukemia and Application to Other Hematologic Malignancies
By
Akihiro Yokoyama,
Junko Okabe-Kado,
Naoki Wakimoto,
Hirofumi Kobayashi,
Akiko Sakashita,
Nobuo Maseki,
Tsuyoshi Nakamaki,
Ken-ichiro Hino,
Shigeru Tomoyasu,
Nobuyoshi Tsuruoka,
Kazuo Motoyoshi,
Naokazu Nagata, and
Yoshio Honma
From the Department of Chemotherapy, Research Institute and
Hematology Clinic, Hospital, Saitama Cancer Center, Saitama, Japan; the
Department of Hematology, Showa University School of Medicine, Tokyo,
Japan; and the Third Department of Internal Medicine, National Defense
Medical College, Saitama, Japan.
 |
ABSTRACT |
The differentiation inhibitory factor nm23 can inhibit the
differentiation of murine and human myeloid leukemia cells. We recently
reported that nm23 genes were overexpressed in acute myelogenous leukemia (AML), and a higher level of nm23-H1
expression was correlated with a poor prognosis in AML, especially in
AML-M5 (acute monocytic leukemia). To evaluate the importance of
nm23 expression as a prognostic factor in AML, we compared it
with other putative prognostic factors in AML. An analysis of the
correlation between nm23 expression and the clinical parameters
of 110 patients with AML demonstrated that increased nm23-H1
mRNA levels were associated with resistance to initial chemotherapy and
with reduced overall survival. Multivariate analysis using Cox's
proportional hazard model also showed that elevated nm23-H1
mRNA levels significantly contributed to the prognosis of patients with
AML. Especially in AML-M5, nm23-H1 status was the most
important prognostic factor. Furthermore, to determine whether we can
apply the results observed in AML to other hematologic malignancies, we
investigated the relative levels of nm23-H1 and nm23-H2
transcripts in 149 patients with hematologic neoplasms, including 110 with de novo AML, 9 with de novo acute lymphoblastic leukemia, 14 with
myelodysplastic syndrome, 16 with chronic myelogenous leukemia (CML),
and 5 normal subjects by the reverse transcriptase-polymerase chain
reaction. Expression of nm23-H1 was significantly higher in all
the hematologic neoplasms, except CML in chronic phase, than in normal
blood cells. nm23 may have a prognostic effect in these
hematologic malignancies as well as in AML.
| |
INTRODUCTION |
ALTHOUGH NORMAL hematopoiesis can be controlled by
various positive and negative regulatory molecules, leukemic cells are arrested in less-differentiated stages of development. This suggests that both positive and negative regulators are important for the differentiation of leukemic cells. We previously reported that a
nondifferentiating mouse myeloid leukemia cell line produced differentiation inhibiting factors (I-factors). Suppression of the
production of these I-factors resulted in nondifferentiating leukemic
cells becoming sensitive to differentiation inducers. One of these
I-factors was purified as a homologue of nm23.1-3
The differentiation inhibitory factor nm23 can inhibit the
differentiation of murine and human myeloid leukemia cells, and nm23 expression is greatly increased during blast formation in normal lymphocytes.1-4 These findings suggest that
nm23 genes play a role in the growth and differentiation of
normal and malignant hematopoietic cells. Few studies have focused on
the role of nm23 in human hematopoietic
malignancies.5 We recently reported that nm23 genes
were overexpressed in acute myelogenous leukemia (AML) and that
nm23-H1 expression was significantly correlated with a poor
prognosis in AML, especially in AML-M5.6 It has been
reported that high-grade non-Hodgkin's lymphoma (NHL) and Hodgkin's
lymphoma exhibited significantly higher levels of nm23-H1 expression than low-grade NHL.7 These studies suggest that nm23-H1 expression in human hematopoietic malignancies is
associated with the aggressiveness of the disease.
In the present study, to evaluate the importance of nm23
expression as a prognostic factor in AML, we compared the levels of
nm23 expression with other putative prognostic factors in AML by a multivariate analysis. Furthermore, to determine whether we can
apply the results observed in AML to other hematologic malignancies, we
examined the expression of nm23-H1 and -H2 genes in
various human hematologic malignancies other than AML.
| |
MATERIALS AND METHODS |
Patients' samples.
Bone marrow (BM) or peripheral blood (PB) samples were obtained from
149 patients with newly diagnosed hematologic neoplasms, consisting of
110 with de novo AML, including 42 previously reported cases,6 9 with de novo acute lymphoblastic leukemia (ALL), 9 with myelodysplastic syndrome (MDS; 1 with chronic myelomonocytic leukemia [CMMoL], 4 with refractory anemia with excess
of blasts [RAEB], and 4 with RAEB-T), 5 with MDS overt
leukemia, 9 with chronic myelogenous leukemia in the chronic phase
(CML-CP), and 7 with CML in blast crisis (CML-BC) with their informed
consent at onset, before chemotherapy. De novo AML, ALL,
and MDS were classified according to the criteria devised by the
French-American-British (FAB) Committee. AML patients were treated with
cytosine arabinoside (or behenoyl cytosine arabinoside), daunorubicin,
and with or without prednisolone and/or 6-mercaptopurine, and
AML-M3 patients were consecutively treated with all-trans
retinoic acid for remission induction therapy.8,9 Treated
patients were judged to have achieved complete remission (CR) when BM
aspirates showed trilineage regeneration with less than 5% blasts by
morphology and immunocytochemistry in the presence of a normal blood
count that persisted for at least 1 month. Patients who died of toxic
complication (infection or bleeding) before the time of expected marrow
recovery were not evaluated. All other patients were considered
nonresponsive (NR). To purify leukemic cells, heparinized PB cells or
BM aspirates were mixed with an equal volume of RPMI-1640 medium and
centrifuged on Ficoll-Hypaque (Pharmacia, Uppsala, Sweden). Normal BM
and PB cells were obtained from healthy volunteers after obtaining their informed consent. Mononuclear cells from normal BM and PB cells
were separated over Ficoll-Hypaque. Total RNA was extracted as
described by Chomczynski and Sacchi, using guanidium
thiocyanate.10
Reverse transcriptase-polymerase chain reaction (RT-PCR).
Quantitative RT-PCR was performed using a GeneAmp RNA PCR kit
(Takara, Tokyo, Japan), as reported previously.6 The
oligonucleotides used in PCR amplification were as follows: sense
strand, 5 -ATGGCCAACTGTGAGCGTACC-3; antisense strand,
5-CATG TATTTCACCAGGCCGGC-3 for nm23-H1; sense strand, 5-ATGGCCAACCTGGAGCGCACC-3; antisense strand,
5-TCCC CACGAATGGTGCCTGGC-3 for nm23-H2; and sense
strand, 5-ACATCGCTCAGACACCATGG-3; antisense strand,
5-GTAGTTGAGGTCAATGAAGGG-3 for glyceraldehyde-3-phosphate dehydrogenase (gapdh). PCR consisted of 35 cycles for
nm23-H1 and 25 for nm23-H2 and gapdh, with
denaturing at 95°C for 1 minute, annealing at 60°C for 1 minute, and extension at 72°C for 0.5 minutes. The reaction was
performed in a GeneAmp PCR system 9600 (Perkin Elmer, Norwalk, CT). The
PCR products were then subjected to 6% polyacrylamide gel
electrophoresis, and the dried gel was exposed to imaging plates (Fuji
Film Co, Ltd, Tokyo, Japan) at room temperature for 15 to 20 minutes.
The results of autoradiography were quantified using a Fuji Bio-Image
Analyzer BAS2000 (Fuji Film Co).
Statistical analysis.
Differences between groups were evaluated by Mann-Whitney's U-test
(nonparametric analysis), and P < 0.05 indicated a
significant difference. Pearson's correlation coefficient was used to
evaluate the correlation between paired values. Survival curves of
patients were prepared by the Kaplan-Meier method, and differences
between the survival curves were evaluated using the log-rank and
generalized Wilcoxon's tests. A multivariate analysis of the prognosis
was performed using Cox's proportional hazard model.
| |
RESULTS |
Relationship between nm23 expression and clinical data in
AML.
We examined the levels of nm23 expression in BM and PB samples
from 110 patients with newly diagnosed de novo AML, including 3 M0, 20 M1, 29 M2, 19 M3, 19 M4, 18 M5 (7 M5a and 11 M5b), and 2 M6. To
normalize the differences in RNA loading for RT-PCR and in RNA
degradation in individual samples, the values of nm23-H1 and -H2 gene expression were divided by that of the
gapdh gene for comparison with the values in erythroleukemia
HEL cells, which were defined as 100 (the expression "Index").
Both nm23-H1 and -H2 genes were overexpressed in these
110 AML samples (Table 1). To evaluate the
relative importance of nm23 expression as a prognostic factor
in AML, we determined the correlation of nm23-H1 or
-H2 expression with age, sex, white blood cell (WBC) count,
lactate dehydrogenase (LDH) level, surface marker CD7, chromosomal
aberration, and the response to initial chemotherapy
(Table 2). Increased LDH was correlated
with nm23-H1 (P = .006) and nm23-H2
expression (P = .038). CD7+ AML showed higher
nm23-H1 expression than CD7 AML (P =
.019). A good response to initial chemotherapy was inversely correlated
with nm23-H1 (P = .020). A total of 100 samples were evaluable in terms of the response to treatment. Thirty-two patients failed to achieve remission after the initial chemotherapy. The drug-resistant AML samples expressed a significantly higher
nm23-H1 level (nm23-H1 index = 144 ± 212)
than those from the 68 AML patients who achieved CR (nm23-H1
index = 97 ± 115). The expression levels of nm23-H1 and
-H2 in AML-M3 leukemia with t(15;17) were lower than those in
the other AMLs without chromosomal aberrations (H1, P
= .010; H2, P = .045; Table 2).
Overall survival in AML.
One hundred three evaluable AML patients were classified into groups
based on age, sex, WBC count, LDH, CD7, chromosomal aberration, and
nm23-H1 and -H2 expression. Overall survival in each
group of patients is shown in Table 3.
There were significant differences in the survival time between the
patients classified by age, WBC count, LDH level, presence or absence
of chromosomal aberration on t(8;21) and t(15;17), and nm23-H1
and -H2 expression levels. Cox's proportional hazard model
was used to evaluate the relative importance of the putative prognostic
factors in Table 3. Of these factors, chromosomal aberration on
t(15;17) and t(8;21) had a good prognostic effect. However, if these
were excluded from a multivariate analysis of the overall survival of
AML patients, nm23-H1 was the most important factor (P = .034, Table 4). Especially in
AML-M5, nm23-H1 mRNA expression significantly contributed to the prognosis, and nm23-H1 status was the most important
prognostic factor (P = .003, Table 4 and
Fig 1). These results showed that the
levels of nm23 gene expression represent a new prognostic factor for AML.
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| Fig 1.
Survival curves of AML-M5 patients. High nm23-H1
(>100) patients (n = 9, solid line) had a worse prognosis than low
nm23-H1 (100) patients (n = 9, broken line)
(generalized Wilcoxon's test, P = .009; log-rank test,
P < .01).
|
|
Application of the expression of the nm23-H1 and -H2 genes to other
hematologic neoplasms.
To apply nm23 expression to hematologic neoplasms other than
AML, we examined the mRNA levels of the nm23-H1 and -H2
genes in hematologic neoplasms, as shown in Table 1 and
Fig 2. The expression levels of the
nm23-H1 gene were significantly higher in MDS (P =
.011), MDS overt leukemia (P = .012), AML (P = .003), ALL (P = .007), and CML-BC (P = .006) than in normal
blood cells. Figure 3 shows the
nm23-H1 and -H2 expression levels in all of the cases.
Although a statistically significant correlation was observed between
the expression levels of nm23-H1 and -H2 (r
= .785, P < .0001), the expression levels of the
nm23-H2 gene were significantly higher in only AML (P =
.023) and CML-BC (P = .013) compared with those in normal blood
cells. The levels of nm23-H1 and -H2 mRNA in CML-CP
cells were similar to the average levels in normal blood cells. With
respect to the clinical stage of hematologic neoplasms, the expression
of both nm23-H1 and -H2 was significantly higher in
CML-BC than in CML-CP (P = .001 and P = .007, respectively), as shown in Fig 4. In
contrast, the expression of both genes in MDS overt leukemia was
similar to the average levels in MDS (P = .205 and P =
.548, respectively; Fig 4). These results indicate that (1)
nm23-H1 is overexpressed in hematologic neoplasms, except CML-CP; (2) this increase in nm23-H1 is observed in the stages of MDS; and (3) the progression of CML is accompanied by the
overexpression of nm23-H1 and -H2 mRNA.
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| Fig 2.
Quantitative RT-PCR analysis of nm23-H1 and
nm23-H2 mRNA in human normal BM cells, MDS, MDS overt leukemia,
AML, ALL, CML-CP, and CML-BC samples. Normal BM cells were from normal
volunteers. Neoplasm cells were identified as the mononuclear cell
fraction.
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| Fig 3.
Relationship between the levels of nm23-H1 and
nm23-H2 in human hematologic neo plasms. (---) Average levels
of normal BM cells; ( ) AML; ( ) ALL; ( ) CML-CP; ( ) CML-BC;
( ) MDS; ( ) MDS overt leukemias
|
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| Fig 4.
nm23-H1 and nm23-H2 expression in MDS in
comparison with MDS overt leukemia and in CML-CP in comparison with
CML-BC. Analyzed by Mann-Whitney's U-test.
|
|
| |
DISCUSSION |
The nm23 gene was originally identified by the differential
hybridization of a cDNA library with total RNA extracted from mildly
and highly metastatic melanoma cell lines.11 Its expression was inversely correlated with the tumor's metastatic potential in
experimental rodent cells and in some human tumors.12
Transfection with nm23 cDNA reduced the metastatic potential in
vivo and the ability of cells to migrate in response to cytokines in
vitro.13-15 Reduced nm23 expression levels are
correlated with increased metastatic potential and an aggressive
disease in human breast,16 hepatocellular,17 ovarian18 and gastric carcinoma,19 and in
melanoma.20 However, an opposite trend is observed in
neuroblastoma and pancreatic carcinoma.21-23 In other tumor
types, including colorectal, thyroid, and lung carcinomas, nm23
expression does not correlate with disease progression.21
These results suggest a functional difference in nm23 gene
expression in several types of human tumor.21 In leukemia,
as shown in this report, nm23 gene expression correlated with a
poor prognosis in AML and with disease progression of CML. Especially
in AML-M5, nm23-H1 mRNA overexpression was the most important
poor prognostic factor (Table 4). These results suggest that there is a
connection between nm23 function and malignant phenotypes in
leukemia, such as malignant growth, differentiation resistance, and
chemotherapy resistance, although it remains unclear why AML-M5 cells
exhibit a higher expression of nm23 nmRNA levels.
We preliminally tried to evaluate the effect of nm23-H1 mRNA
level on prognosis for each of the FAB subtypes, although each group is
a small cohorts of patients. For FAB-M5, there were 9 nm23 low
versus 9 nm23 high; as shown in Fig 1 and Table 4, the elevated
nm23-H1 expression in FAB-M5 significantly contributed to the
prognosis, and nm23-H1 status is the most important prognostic factor. For FAB-M4, there were 12 nm23 low versus 4 nm23 high; the elevated nm23-H1 expression in FAB-M4
significantly predicts a poor response to initial therapy (CR ratios of
nm23 low expression group and nm23 high group were
83.3% and 25.0%, respectively; P = .029,  2
test for independence). The correlation between elevated
nm23-H1 expression and poor survival was observed in M4 cases,
but the statistical significance has not been observed yet. For FAB-M3, there were 15 nm23 low versus 0 nm23 high; theses cases
showed the lowest expression levels of nm23-H1 among FAB
subtypes. Because all cases showed nm23-H1  100 (low
expression), we could not analyse the effect of the
overexpression of nm23-H1 (>100) on overall survival. The
low expression levels of nm23-H1 in FAB-M3 may be associated
with the good prognosis in M3 patients. For FAB-M2, there were 18 nm23 low versus 9 nm23 high; the correlation between elevated nm23-H1 expression and a poor response to initial
therapy and poor survival was observed, but the statistical
significance was not shown. For FAB-M1, there were 12 nm23 low
versus 8 nm23 high; the elevated nm23-H1 expression in
these cases did not contribute to the response to initial therapy and
the prognosis, although FAB-M1 cases had significantly higher
expression levels of nm23-H1 and nm23-H2 than did
normal subjects. Therefore, further analysis of nm23-H1 and
nm23-H2 mRNA levels on prognosis for each of FAB subtypes in
lager cohorts is required.
nm23-H1 and -H2 show 88% amino acid sequence
homology24,25 and are located on the same region of
chromosome 17q21 in tandem.26-28 Based on an analysis of
the promoter regions of the nm23-H1 and -H2 genes, it
has been suggested that these nm23 genes are independently and
differentially regulated.29 However, a statistically
significant correlation between the expression levels of nm23-H1
and -H2 was observed in AML (Fig 3). Elevated expressions
of both nm23 genes were observed in AML, whereas a poor
prognosis and a low percentage of CR in AML were associated only with
the nm23-H1 expression level. Postel et al30
reported that nm23-H2 was a transcription factor (PuF) and that
one of its targets was the c-myc gene. Overexpression of
the c-myc gene has also been reported to inhibit the differentiation of
human and mouse leukemia cells.31-33 However, in our
previous experiment, we did not find a correlation between c-myc
expression and nm23-H2 expression in AML.6 Thus,
c-myc expression in AML does not appear to be influenced by the
overexpression of nm23-H2 (PuF).
Drug resistance, either inherent or acquired, is an important cause of
treatment failure in hematologic neoplasms. Ferguson et
al34 reported a functional link between nm23
expression and cancer cell sensitivity to the alkylating agent
cisplatin. We investigated, mdr1, mrp,
gst- , topo I, topo
II , and topo II expression
in 20 AML patients by RT-PCR, but none of these drug resistance-related
genes were associated with nm23-H1 expression (data not shown).
Other mechanisms may be involved in drug resistance. nm23 genes
can modulate differentiation, proliferation (cell cycle), and drug
resistance in AML, and these three events are closely linked. Inducing
differentiation in leukemic cells is associated with the concomitant
block of the cell cycle at the G0/G1 phase. Transforming growth
factor- (TGF-) is a negative regulator of proliferation, induced
growth arrest in the G1 phase of the cell cycle in many cell types, and
the loss of the cellular response to this ligand that occurs during
oncogenesis in some systems. Transfection of melanoma
K-1735 TK and breast carcinoma MDA-MB-435 cells with
the nm23 gene decreases the response to
TGF-.13,14 We previously isolated a
differentiation-resistant mouse myeloid leukemia M1 cells from the
parent differentiation-sensitive M1 cells. We then characterized the
differentiation-resistant cells and showed that the
differentiation-resistant cells had higher leukemogenicity and produced
I-factors/nm23 more than the parent differentiation-sensitive M1 cells.
The differentiation-resistant M1 cells showed a more progressive
potential, which was resistant to not only differentiation-induction
but also to growth-suppressive cytokines such as
TGF-.33,35-37 The role of nm23 expression in the
malignant growth of leukemia cells remains to be clarified, but
nm23 may play key roles in various aspects of hematopoietic cell biology, including differentiation, proliferation (cell cycle), and drug resistance.
MDS expressed higher nm23-H1 mRNA levels, and this level was
similar to that in AML (Table 1 and Fig 4). In this study, MDS included
CMMoL, RAEB, and RAEB in transformation (RAEB-T), but excluded RA and
RA with ringed sideroblasts (RARS). Although it is necessary to study
RA and RARS (low-risk MDS), this study indicated that, if there were at
least 11% blasts in marrow, nm23-H1 expression could be
detected at the leukemic level by RT-PCR.
The median survival time in CML is 3 to 4 years. Acute transformation
may occur rapidly over weeks or even days. These patients are usually
refractory to conventional chemotherapy. These clinical features seem
to be associated with the elevation of nm23 expression (Table 1
and Fig 4). Recently, Venturelli et al38 isolated a novel
cDNA DR-nm23 that was differentially expressed in a CML blast
crisis cDNA library. The sequence of DR-nm23 is highly similar to that of nm23, and DR-nm23 inhibits granulocyte
differentiation and induces apoptosis in 32Dc13 myeloid cells. These
results suggest that the nm23 family, which includes
DR-nm23, plays an important role in CML blastic crisis as well
as in AML.
Cox's proportional hazard model indicated that the chromosomal
aberrations t(15;17) and t(8;21) had good prognostic value, but they
were limited to just AML-M3 and AML-M2. Because the prognostic evaluation of nm23 is applicable to all stages of AML,
nm23-H1 status will be the most important prognostic factor.
Furthermore, because the overexpression of nm23-H1 is also
observed in other hematologic malignancies, such as ALL and MDS,
nm23 expression could also have prognostic value in these
diseases.
| |
FOOTNOTES |
Submitted October 20, 1997;
accepted December 10, 1997.
Supported in part by a grant from the Ministry of Health and
Welfare, Grants-in-Aid for Scientific Research (C) and Cancer Research;
a grant from the Ministry of Education, Science, Sports and Culture,
Japan; and a grant from the Kawano Memorial Foundation for the
Promotion of Pediatrics.
Address reprint requests to Junko Okabe-Kado, PhD, Department of
Chemotherapy, Saitama Cancer Center Research Institute, 818 Komuro,
Ina, Saitama 362-0806, Japan.
The publication costs of this article were defrayed in part by
page charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors gratefully acknowledge Dr Yoshiharu Hoshiyama (Showa
University School of Medicine, Tokyo, Japan) for helpful discussions in
statistical analysis.
| |
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Abstract
Introduction
Abstract