Expression of cell surface NM23 proteins of human leukemia cell lines of various cellular lineage and differentiation stages

Leukemia Research 26 (2002) 569–576

Expression of cell surface NM23 proteins of human leukemia cell lines of various cellular lineage and differentiation stages Junko Okabe-Kado∗ , Takashi Kasukabe, Yoshio Honma Saitama Cancer Center Research Institute, 818 Komuro, Ina, Kita-adachi, Saitama 362-0806, Japan Received 5 June 2001; accepted 2 October 2001

Abstract Cell surface expression of NM23 protein is only observed on tumor cell lines, but not on normal cells. To examine what types of tumor cell line express the cell surface NM23 protein, we measured the cell surface NM23-H1 and NM23-H2 proteins of leukemia line cells on various cellular lineage and differentiation stages. The NM23-H1 was expressed on myeloid leukemia lines but not lymphoid lines, while NM23-H2 was only expressed on erythroleukemia lines. The complement-dependent cytolysis confirmed the expression of these proteins on the surface. Surface NM23-H1 and NM23-H2 proteins were decreased during in vitro erythroid and granulocyte differentiation. These results show that the surface expression of NM23 proteins is related to cellular lineage and differentiation stage of leukemia line cells. © 2002 Elsevier Science Ltd. All rights reserved. Keywords: Cell surface proteins; NM23-H1; NM23-H2; Leukemia cells; Differentiation; Flow cytometry

1. Introduction The nm23 family of genes was discovered on the basis of its reduced expression in highly metastatic murine melanoma cell lines, compared with related but less metastatic melanoma cell lines [1]. Reduced nm23 expression has been correlated with reduced patient disease-free or overall survival and with other histopathologic indicators of high metastatic potential in cohorts of breast, ovarian, cervical, gastric and hepatocellular carcinomas and melanoma [2]. High homology between NM23 proteins and NDPK in a number of species has been identified [2]. In humans, eight nm23 isotypes (nm23-H1, nm23-H2, nm23-H3/DR-nm23, nm23-H4, nm23-H5, nm23-H6, nm23-H7, and nm23-H8) have been identified to date [3]. We found that a differentiation inhibitory factor purified from conditioned medium of a differentiation-resistant mouse myeloid leukemia cell line was identical to the Abbreviations: NDPK, nucleoside diphosphate kinase; AML, acute myelogenous leukemia; mAb, monoclonal antibodies; GA, glycophorin A; BSA, bovine serum albumin; FITC, fluorescein isothiocyanate; TGF-␤1, transforming growth factor-␤1; ATRA, all-trans retinoic acid; TPA, 12-O-tetradecanoylphorbol-13-acetate; VD3, 1␣,25-dihydroxyvitamin D3; PB, peripheral blood ∗ Corresponding author. Tel.: +81-48-722-1111; fax: +81-48-722-1739. E-mail address: [email protected] (J. Okabe-Kado).

NM23 protein [4–7]. The nm23 genes are overexpressed in AML cells, and a higher level of nm23 expression is correlated with a poor prognosis in AML [8–10]. Recently, we have determined the plasma level of NM23-H1 protein by enzyme-linked immunosorbent assay and assessed the association between this level and the clinical outcome in patients with AML [11,12]. The plasma concentration of NM23-H1 was higher in patients with AML than in normal controls, and elevated plasma NM23-H1 levels significantly contributed to the prognosis of AML patients. These results suggest that both cellular and extracellular levels of NM23-H1 in AML play an important role in leukemia cell differentiation and clinical outcome in patients with AML. The highest intracellular levels of NM23 proteins were contained in AML cells, a number of tumor cell lines, and normal bone marrow CD34+ progenitors. Lower levels of intracellular NM23 proteins were measured in more mature bone marrow cells, whereas peripheral blood leukocytes had the lowest expression. Thus, a decrease in expression levels of intracellular NM23 was observed upon maturation of hematopoietic cells [13]. However, extracellular cell surface expression of NM23 was only observed on tumor cell lines and was not detected on normal hematopoietic cells [13,14]. Although there are a lot of papers concerning the expression of intracellular NM23 proteins, we have little

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information concerning extracellular expression, especially cell surface expression. In this paper, to examine what types of tumor cell lines express the cell surface NM23 protein, we measured the cell surface NM23-H1 and NM23-H2 proteins of leukemia cell lines of various cellular lineage and differentiation stages.

PBS containing 1% BSA at 4 ◦ C for 30 min. The cells were washed with PBS and incubated in 100 ␮l of 1% FITC-conjugated anti-mouse IgG (TAGO Immunologicals, Camarillo, CA, USA) in PBS containing 1% BSA at 4 ◦ C for 30 min, washed with PBS and then analyzed in an Epics XL flow cytometer (Coulter Electronics).

2. Materials and methods

2.4. Induction of differentiation and apoptosis of leukemia cells

2.1. Cell lines and cell culture We used human monoblastic leukemia U937 [15], THP-1 [16], and HEL/S [17] cell lines, a myelomonocytic leukemia ML-1 [18] cell line, promyelocytic leukemia HL60 [19], NB4 [20], HT93 [21] cell lines, erythrocytic leukemia HEL [22], K562 [23], KU812F [24], M6 cell lines, B-type leukemia/lymphoma HT [25], DB [25], BALM-3 [26], SKW-4 [27], SU-DHL-4 [28], U698-M [29], Raji [30], BALM-1 [31], BALL-1 [32] cell lines, and T-type lymphocytic leukemia MOLT4 [33], MOLT16 [34], Jurkat [35], HPB-ALL [36] cell lines. HEL/S is a subclone which isolated from HEL and has monoblastic feature [17]. M6 is an erythroleukemia cell line which we established from bone marrow mononuclear cells of a patient with acute erythroleukemia and have maintained in continuous culture since 1997. All of the human leukemia cells were maintained at 37 ◦ C under 5% CO2 in RPMI (Life Technologies Inc., Grand Island, NY, USA) supplemented with 10% fetal bovine serum. The cell number was counted in a model ZM Coulter Counter (Coulter Electrics, Luton, UK). 2.2. Antibodies Monoclonal antibodies against NM23-H1 and NM23-H2 were obtained from Seikagaku Kogyo Co. (Tokyo, Japan). The mAb H1-229 specific for NM23-H1 protein and mAb H2-439 specific for NM23-H2 protein were used for flow cytometrical analysis, and H2-206 for NM23-H2 protein was used for complement-dependent cytotoxicity assay. These mAbs were generated by using the GST-fusion proteins for immunization of mice as previously described [14]. Mouse immunoglobulin IgG2a , IgG1 and IgG2b were used as the isotype-matched control immunoglobulin for the H1-229, H2-439, and H2-206, respectively. Anti-GA was purchased from DAKO JAPAN (Kyoto, Japan), and anti-CD11b, anti-CD14, and anti-CD33 were from Nichirei Co., Tokyo, Japan. 2.3. FACS analysis The expression of surface NM23-H1 and NM23-H2 proteins of leukemia line cells was analyzed by indirect immunofluorescent staining and flow cytomery [14]. Briefly, leukemia cells (1 × 106 cells) were washed with cold PBS and incubated in 100 ␮l of 1% H1-229 or 1% H2-439 in

To assay erythroid differentiation of leukemia cells, K562, HEL and KU812F cells (5 × 104 cells/ml) were cultured with various concentrations of a differentiation-inducing agent for 4–5 days. As erythroid-differentiation inducers, we used sodium butyrate for K562 cells, TGF-␤1 for KU812F and HEL, and hemin for K562 and HEL cells [37,38]. TGF-␤1 was purchased from R&D Systems (Minneapolis, MN, USA); sodium butyrate and hemin were purchased from Sigma (St. Louis, MO, USA). The expression of erythroid marker GA on the surface was determined by indirect immunofluorescent staining and flow cytometry. To assay the granulocytic differentiation of leukemia cells, NB4 cells were cultured with 4 × 10−8 M ATRA for 4 and 9 days. The induction of CD11b expression and the decrease of CD33 expression on the surface were determined by flow cytometry. The monocytic differentiation was induced in HL60 cells by the treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA, Consolidated Midland, Browser, NY, USA) or 1␣,25-dihydroxyvitamin D3 (Chugai Pharmaceutical Co., Tokyo, Japan), and was measured by the induction of CD14 expression. Morphologic differentiation was also evaluated in cell smears stained with May–Gruenwald–Giemsa. To induce the apoptosis, HL60 cells were treated with actinomycin D [39]. 2.5. Complement–dependent cytotoxicity by monoclonal antibodies HL60 (surface NM23-H1+ H2− type) and HEL (surface NM23-H1+ H2+ type) cells were suspended in Cedarlane cytotoxicity medium (Cedarlane Laboratories Ltd., Ont., Canada) at a cell concentration to 1 × 106 cells/ml. Two mAbs, H1-229 (IgG2a ) specific for NM23-H1 protein and H2-206 (IgG2b ) specific for NM23-H2 protein (Seikagaku Kogyo, Tokyo, Japan) were added, and the solution was mixed and incubated for 60 min at 4 ◦ C. After centrifugation to pellet cells, the cells were resuspended to the original volume in Cedarlane cytotoxicity medium containing the 20% Cedarlane low-Tox-M rabbit complement, incubated for 60 min at 37 ◦ C and placed on ice. The dead cells were scored in a hemocytometer using trypan blue. Cytotoxic index (CI) can be calculated as follows: cytotoxicity(antibody + complement) − cytotoxicity(complement alone) CI = × 100 100 − cytotoxicity(complement alone)

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3. Results 3.1. Cell surface NM23 proteins on various leukemia cell lines We first examined the NM23 proteins expressed on the cell surface of various leukemia cell lines using monoclonal antibody specific for NM23-H1 (H1-229), since it has been reported that this antibody is reactive with some human leukemia cell lines by flow cytometry and there is cellular heterogeneity in terms of cell surface expression of NM23 in some cell lines. To examine the relation between the surface expression of NM23 protein and both the cellular lineage and cellular differentiation, we used various human leukemia/lymphoma cell lines (U937, THP-1, HEL/S, ML-1, HL60, NB4, HT93, HEL, K562, KU812F, M6, BALM-3, SKW-4, SU-DHL-4, U698-M, Raji, BALM-1, BALL-1, MOLT4, MOLT16, Jurkat, and HPB-ALL). The results are summarized in Table 1 and the representative patterns in flow cytometry of leukemia cell lines are shown in Fig. 1. Moreover, cell surface NM23-H1 expression associated with CD33, but not CD3 or CD19 expression on leukemia cells (data not shown). These results indicate that

Fig. 1. Cell surface expression of NM23-H1 protein of various leukemia cell lines. The cells were incubated with mAb H1-229 specific for NM23-H1 protein (solid), and the bound antibody was detected with an FITC-labeled antibody to mouse IgG by flow cytometry. As a control (open), the cells were incubated with IgG2a .

Table 1 Cell surface NM23 on various leukemia and lymphoma cell lines Cell lines

Cell type

Original diagnosis

NM23-H1a

NM23-H2a

Myeloid HL-60 NB4 HT93 ML-1 THP-1 U937

Promyelocytic Promyelocytic Promyelocytic Myelomonocytic Monoblastic Monoblastic

AML-M2 AML-M3 AML-M3 AML-M4 AML-M5 Histiocytic lymphoma

+ ++ ++ + ++ ++

− − − − − −

Erythroid K562 KU812F HEL M6

Erythroid-megakaryocytic Erythroid Erythroid-megakaryocytic Erythroid-megakaryocytic

CML-BCb CML-BC AML-M6 AML-M6

++ ++ ++ ++

++ ++ ++ ++

Lymphoid BALL-1 BALM-1 HT DB BALM-3 SKW-4 SU-DHL-4 U-698-M Raji MOLT4 MOLT16 Jurkat HPB-ALL

B B B B B B B B B T T T T

ALLc ALL Malignant lymphoma Malignant lymphoma Malignant lymphoma Malignant lymphoma Malignant lymphoma Lymphoblastic lymphosarcoma Burkitt lymphoma ALL ALL ALL ALL

− − − − − − − − +/− − − − −

− − − − − − − − − − − − −

cell cell cell cell cell cell cell cell cell cell cell cell cell

a Cell surface expression of NM23-H1 and NM23-H2 proteins was examined by flow cytometry with mAb H1-229 and H2-439, respectively. Results are classified into − to ++ depending on the intensity of reactivities by flow cytometry. Fluorescence intensity; −, ≤0.33; +/−, 0.33–0.5; +, 0.5–1.0; ++,≤1.0. b Chronic myelogenous leukemia in blastic crisis. c Acute lymphocytic leukemia.

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most myeloid leukemia cell lines, but not lymphoid cell lines, express the NM23-H1 protein on their cell surface. On the other hand, mAb specific for NM23-H2 was only reactive with the erythroleukemia cell lines, such as K562, KU812F, HEL and M6 (Table 1). Cell surface NM23-H2 expression was associated with GA expression on leukemia cells (data not shown). These results indicate that (1) cell surface NM23-H1 protein is widely expressed on myeloid leukemia cell lines, and (2) cell surface expression of NM23-H2 protein on leukemia cell lines is restricted to those of erythroid lineage. 3.2. Cell surface NM23 proteins and cellular kinetics Based on the surface expression of NM23, cells were classified as NM23-H1+ H2− , NM23-H1+ H2+ or NM23-H1− H2− . As shown in Table 1, all of the human myeloid leukemia cell lines tested were NM23-H1+ H2− types, and all of the erythroleukemia cell lines were NM23-H1+ H2+ types. We investigated the cell surface NM23 expression of HEL (NM23-H1+ H2+ type) and HL60 (NM23-H1+ H2− type) on various growth stages and cell densities. The expression levels of cell surface NM23-H1 and NM23-H2 on cell lines during growth was stable, while it slightly increased when the cell density reached saturation (data not shown). Surface NM23 expression was not altered during serum starvation or during actinomycin D-induced apoptosis of HL60 cells, although the antibodies were nonspecifically reactive with dead cells by flow cytometry (data not shown). These results show that cellular kinetics, such as growth stages, saturation density, serum-starvation, and apoptosis, hardly affect the expression of cell surface NM23 protein.

Fig. 2. Induction of complement-dependent cytolysis in leukemia cell lines using cell surface NM23 proteins. (A) HL60 (NM23-H1+ H2− type) cells; (B) HEL (NM23-H1+ H2+ type) cells were incubated with mAb H1-229 or mAb H2-206, and then with complement. The dead cells were scored in a hemocytometer using trypan blue. The results are representative of three independent experiments each done in duplicate and the S.D. are less than 20%.

3.3. Cell surface NM23 protein as a target of complement-dependent cytolysis We tried to use cell surface NM23 protein as a target of complement-dependent cytolysis using monoclonal antibody specific for NM23-H1 (H1-229, immunoglobulin class IgG2a ) and NM23-H2 (H2-206, immunoglobulin class IgG2b ). Cytolysis was induced in HL60 (NM23-H1+ H2− type) cells by NM23-H1 antibody and complement, but not by NM23-H2 antibody (Fig. 2A). Cytolysis was induced in HEL (NM23-H1+ H2+ type) cells by treatment with either NM23-H1 antibody or NM23-H2 antibody in the presence of complement (Fig. 2B). These results indicate that we confirmed the expression of these proteins on the surface and suggest that the surface NM23 protein might be a molecular target of leukemia therapy. 3.4. Cell surface NM23 proteins during the erythroid differentiation of leukemia cells Normal PB cells do not have cell surface NM23 proteins [13,14], while all myeloid leukemia cell lines do (Table 1).

Fig. 3. Cell surface NM23 proteins during the erythroid differentiation of K562 cells. (A) The expression patterns (solid) of NM23-H1, NM23-H2 and GA on cells treated with or without sodium butyrate by flow cytometry. As a control (open), the cells were incubated with IgG2a for NM23-H1, IgG1 for NM23-H2 and GA, respectively. Sodium butyrate enhanced the expression of GA (right panel), a marker of erythroid differentiation, and decreased the expression of both NM23-H1 (left panel) and NM23-H2 (center panel). (B) The decreases in the expression levels (left panel) of both NM23-H1 and NM23-H2 during erythroid differentiation (right panel). The results are representative of three different experiments.

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Therefore, we next examined the expression of cell surface NM23 proteins during the differentiation of K562 and HEL cells, since these cells were reactive with both NM23-H1 and NM23-H2 proteins and erythroid differentiation could be induced by some agents. Sodium butyrate and TGF-␤1 induce the erythroid differentiation of K562 and HEL cells, respectively. Sodium butyrate enhanced the expression of GA, a marker of erythroid differentiation, and decreased the expression of both NM23-H1 and NM23-H2 on K562 cells (Fig. 3). The expression of surface NM23-H1 and NM23-H2 protein also decreased during the TGF-␤1-induced erythroid differentiation of HEL cells (data not shown). Hemin, which induces erythroid differentiation in HEL and K562 cells, also induced erythroid differentiation and decreased the expression of cell surface NM23 proteins in a dose-dependent manner (data not shown). These results indicate that the expression levels of cell surface NM23 proteins decrease during in vitro erythroid differentiation. Downregulation of cell surface NM23 protein expression during the in vitro erythroid differentiation of leukemia cells is consistent with the normal maturation of erythroid cells, since normal peripheral blood erythrocytes do not react with NM23 antibodies [13,14]. Thus, cellular heterogeneity in terms of the cell surface expression of NM23 in leukemia cell lines is related to cellular lineage and differentiation stage. 3.5. Cell surface NM23 protein during the granulocytic and monocytic differentiation of leukemia cells We next examined the expression of cell surface NM23H1 proteins during the granulocytic differentiation of

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promyelocytic leukemia NB4 cells (NM23-H1+ H2− type) induced by ATRA. Treatment with 4 × 10−8 M ATRA for 9 days induced the expression of CD11b (Fig. 4), morphological differentiation and nitroblue tetrazolium-reducing activity (data not shown). The expressions of NM23-H1 and CD33 decreased during the granulocytic differentiation of NB4 cells (Fig. 4). Although treatment with 4 × 10−8 M ATRA for 4 days also induced the expression of CD11b and nitroblue tetrazolium-reducing activity, it did not decrease the expression of either NM23-H1 or CD33 (data not shown). These results suggest that the cell surface NM23-H1 protein is expressed in the immature granulocyte stage of leukemia cells and disappears in their granulocytic maturation. TPA and VD3 induced the monocytic differentiation of HL60 cells. We did not find any decrease in the expression level of surface NM23-H1 (data not shown). Thus, TPA- or VD3-induced CD14-positive HL60 cells seem to be different from normal PB monocytes in terms of cell surface NM23 protein.

4. Discussion We previously reported a differentiation-inhibiting factor (I-factor) which was detectable in the membrane fraction and in the culture medium of differentiation-resistant mouse myeloid leukemia M1 cells [5]. The amino acid sequence of I-factor fragments was identical to that of NM23 protein [6]. The nm23 genes are overexpressed in AML cells, and a higher level of NM23-H1 expression and a higher plasma

Fig. 4. Cell surface NM23 protein during the granulocytic differentiation of NB4 cells. NM23-H1+ H2− type promyelocytic leukemia NB4 cells were treated with 4 × 10−8 M ATRA. (A) The expression levels of CD11b, CD33, NM23-H1, and NM23-H2 were examined. (B) The expression patterns of CD11b, NM23-H1, and CD33 on cells treated with (solid) or without (open) ATRA by flow cytometry. The results are representative of three different experiments.

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concentration of NM23-H1 protein significantly contribute to the prognosis of AML patients [8–10,12]. Both the cellular and extracellular levels of NM23 in AML play an important role in leukemia cell differentiation and the clinical outcome in patients with AML. These results agree with our findings that I-factor proteins are present in the membrane fraction and in the culture medium of differentiationresistant and highly leukemogenic mouse myeloid leukemia M1 cells [4–6]. There was no relationship between intracellular levels and cell surface expression levels of NM23 protein. For example, all of the leukemia cell lines had higher levels of intracellular NM23-H2 [8,9], but only erythroleukemia cell lines expressed the cell surface NM23-H2 protein. Willem et al. has studied both intracellular and cell surface expression of NM23 in hematopoietic tissues using flow cytometry. They demonstrated that intracellular NM23 proteins were highly expressed in normal hematopoietic progenitors, while the cell surface NM23 proteins were not detected on these normal cells. Cell surface expression of NM23 protein was only observed on tumor cell lines [13,14]. These results suggest that the surface expression of NM23 proteins depends on the cell type, but not on intracellular NM23 expression levels. In this report, we showed the surface expression of NM23 protein was related to cellular lineage and differentiation stage of leukemia cell lines. Most myeloid leukemia cell lines, which expressed CD33, expressed the NM23-H1 protein on their cell surface (Table 1). Among these myeloid cell lines, tended to be a correlation between NM23-H1 and CD33 expression levels. The expression level of cell surface NM23-H1 protein in NB4 cells decreased during in vitro ATRA-induced granulocytic differentiation, accompanied by a decrease in the CD33 level. Normal PB mature granulocytes did not have cell surface NM23-H1 protein and CD33. Therefore, these results suggest that the cell surface NM23-H1 protein level is related to cellular differentiation, especially granulocytic differentiation stages with CD33 before maturation. Cell surface NM23-H2 was detected only on the erythroleukemia cell lines, such as K562, KU812F, HEL and M6, which express GA, CD33 and CD41, a marker of megakaryocytic differentiation (data not shown). Among these cell lines, the expression level of NM23-H2 was correlated with that of GA and also that of CD41 (data not shown). The nm23-H1 and nm23-H2 genes encode the family of NDPK, which transfer the terminal phosphate of nucleoside triphosphates to nucleoside diphosphates [1,40,41]. Using enzymatic assays, surface-bound NDPK has been observed on platelets [42]. Table 1 shows that the NM23-H1+ H2+ type cell lines are restricted to the erythroid/megakaryocytic leukemia lines. These results suggest that NM23-H2 protein play a role in the function of these cells. NM23-H1 and NM23-H2 proteins have NDPK activity [1,40,41]. It would be interesting to determine whether cell surface NM23 proteins function as ecto-nucleoside diphos-

phate kinases, as shown in human astrocytoma cells [43]. NM23 proteins have been reported to be associated with other proteins; transcription factors such as the retinoic acid receptor-related orphan receptor ␣ and the retinoic Z receptor ␤, the heat shock protein Hsc70, and telomeres [44–46]. NM23 protein also reportedly has protein kinase activity [47–49]. It is unknown whether the cell surface NM23 proteins are associated with other extracellular proteins, or whether they have protein kinase activity. NM23 molecules have many biological activities and are ubiquitously distributed in many tissues. The main biological roles of NM23 may depend on the cell lineage or differentiation/ developmental stage, and on their subcellular/extracellular localization. The molecular mechanisms of the surface expression of NM23 proteins are unknown. They might be expressed via intracellular transport following their synthesis, or may be shed from cells and then attached to the cell surface following an autocrine mechanism. In fact, we have found NM23 proteins in culture supernatants of myeloid leukemia cell lines and plasma of patients with AML [12]. We are now trying to detect the cell surface NM23 proteins of PB mononuclear cells from patients with AML.

Acknowledgements This work was supported in part by grants-in-aid from the Ministry of Health and Welfare for the Second Term Comprehensive 10-Years Strategy for Cancer Control, and grants-in-aid for Scientific Research (C) and Cancer Research, from the Ministry of Education, Science, Sports and Culture, Japan. J. Okabe-Kado provided the concept, design, assembled and analyzed the data, drafted and revised the manuscript and provided the necessary funding. T. Kasukabe provided technical support, study materials, assisted with data analysis and the revision. Y. Honma contributed to the provision of materials, data collection and analysis, revision of the paper and provided funding for the project.

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