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Subclassification of Patients with Acute Myelogenous Leukemia Based On Research Paper Subclassification of patients with acute myelogenous leukemia based on chemokine responsiveness and constitutive chemokine release by their leukemic cells Øystein Bruserud, Anita Ryningen, Astrid Marta Olsnes, Laila Stordrange, Anne Margrete Øyan, Karl Henning Kalland, Bjørn Tore Gjertsen ABSTRACT From the Division for Hematology, Background and Objectives Department of Medicine, Haukeland University Hospital Chemokines are soluble mediators involved in angiogenesis, cellular growth control and The University of Bergen, and immunomodulation. In the present study we investigated the effects of various Bergen, Norway (OB, AR, AMartO, chemokines on proliferation of acute myelogenous leukemia (AML) cells and consti- BTG); Department of Informatics, tutive chemokine release by primary AML cells. The University of Bergen, Norway (LS); The Gade Institute, Haukeland Design and Methods University Hospital and The Native human AML cells derived from 68 consecutive patients were cultured in vitro. University of Bergen, Norway 3 (AMargO, KHK). We investigated AML cell proliferation ( H-thymidine incorporation, colony formation), chemokine receptor expression, constitutive chemokine release and chemotaxis of Funding: this work was supported by normal peripheral blood mononuclear cells. the Norwegian Cancer Society. Results Acknowledgments: the technical Exogenous chemokines usually did not have any effect on AML blast proliferation in assistance of Kristin Paulsen and the absence of hematopoietic growth factors, but when investigating growth factor- Aina Kvinsland is gratefully acknowl- dependent (interleukin 3 + granulocyte-macrophage colony-stimulating factor + stem edged. cell factor) proliferation in suspension cultures the following patient subsets were identified: (i) patients whose cells showed chemokine-induced growth enhancement Manuscript received April 11, 2006. Manuscript accepted February 5, (8 patients); (ii) divergent effects on proliferation (15 patients); and (iii) no effect 2007. (most patients). These patient subsets did not differ in chemokine receptor expres- sion, but, compared to CD34– AML cells, CD34+ cells showed higher expression of Correspondence: several receptors. Chemokines also increased the proliferation of clonogenic AML Øystein Bruserud, Medical cells from the first subset of patients. Furthermore, a broad constitutive chemokine Department, Haukeland University release profile was detected for most patients, and the following chemokine clusters Hospital, N-5021 Bergen, Norway. could be identified: CCL2-4/CXCL1/8, CCL5/CXCL9-11 (possibly also CCL23) and E-mail: oystein.bruserud@hauke- CCL13/17/22/24/CXCL5 (possibly also CXCL6). Only the CCL2-4/CXCL1/8 cluster land.no showed significant correlations between corresponding mRNA levels and NFκB lev- els/activation. The chemotaxis of normal immunocompetent cells for patients with- out constitutive chemokine release was observed to be decreased. Interpretation and Conclusions Differences in chemokine responsiveness as well as chemokine release contribute to patient heterogeneity in AML. Patients with AML can be classified into distinct sub- sets according to their chemokine responsiveness and chemokine release profile. key words: acute myelogenous, leukemia, chemokine, NFKB, CXCR2 Haematologica 2007; 92:332-341 ©2007 Ferrata Storti Foundation | 332 | haematologica/the hematology journal | 2007; 92(03) Chemokine networks in AML hemokines are a family of soluble proteins that are units by the AML cells was analyzed using flow cytome- involved in a wide range of biological processes try, as described in the supplementary section. Anti- Cwith relevance for hematologic malignancies, CXCR2-FITC, anti-CXCR3A-PE; anti-CXCR4-APC, anti- including cell trafficking, regulation of cell proliferation CCR3-FITC; anti-CCR1-PE; anti-CCR5-APC, anti-CCR4- and apoptosis, immunoregulation, normal hematopoiesis FITC, anti-CCR2-PE and their corresponding isotypic con- and angiogenesis.1-5 The chemokines are grouped into the trols were all purchased from R&D Systems (Abingdon, two major subclasses, CCL and CXCL chemokines, UK). Anti-CXCR1-APC, an alternative anti-CXCR2-FITC, which interact with CCR and CXCR membrane recep- anti-CD34-PerCP and corresponding isotype controls tors, respectively. Another classification of chemokines is: were purchased from Becton Dickinson Immuno- (i) homeostatic (also called constitutive) chemokines that cytometry Systems (San Jose, CA, USA). PE-conjugated bind to single receptors; and (ii) inflammatory (also called antibodies and isotype controls against the NFκB subunits inducible) chemokines that bind to several receptors, and p50, p52 and p65 were supplied by Santa Cruz each of these receptors can usually bind several Biotechnology Inc. (Santa Cruz, CA, USA). chemokines.1-5 Acute myelogenous leukemia (AML) is an aggressive In vitro culture of human AML cells disorder characterized by accumulation of immature Reagents. The Stem Span SFEM™ culture medium malignant cells in the bone marrow.6 The overall disease- (referred to as Stem Span™; Stem Cell Technologies; free survival for younger patients (<60 years of age) Vancouver, BC, Canada) supplemented with 100 µg/mL receiving the most intensive conventional chemotherapy of gentamicin was used in all experiments.11,12,15 is less than 50%.6 However, AML is a very heterogeneous Recombinant human cytokines were purchased from disorder,6-10 and the recently published WHO classification Peprotech (London, UK) except for CXCL14 that was pur- is, therefore, based on a combination of clinical history chased from R&D Systems. Chemokines were used at a (predisposition due to preleukemic disorders or previous final concentration of 20 ng/mL and hematopoietic chemotherapy), morphology and cytogenetic abnormali- growth factors (interleukin-3, IL3; stem cell factor, SCF; ties.9 Patients can thereby be subclassified according to granulocyte-macrophage colony-stimulating factor, GM- prognosis, i.e. risk of primary chemoresistance or later CSF) at 50 ng/mL. Bortezomib was purchased from AML relapse. We have previously described that Jansen-Cilag (Beerse, Belgium) and BMS-345541 from cytokine-induced, receptor-mediated phosphorylation Sigma Aldrich (St. Louis, MO, USA). Both drugs were dis- patterns of intracellular mediators can also identify sub- solved in DMSO and later in culture medium. Pilot exper- sets of patient with different prognoses.10 Furthermore iments demonstrated that bortezomib 25 nM caused CXCR4 expression was recently described to have a prog- strong inhibition of cytokine-dependent AML cell prolif- nostic impact in AML.7 However, chemokines and their eration and the drug was used at this concentration. BMS- receptors form a complex network and it is therefore rel- 34551 was used at a final concentration of 10 µM.16 evant to focus also on chemokine profiles and not only Proliferation assay. AML blasts (5×104 cells/well) were single chemokines. In the present study we investigated cultured in flat-bottomed microtiter plates in Stem Span™ the release of a wide range of chemokines from primary (150 µL per well; Costar 3596 culture plates; Costar, human AML blasts and these cells’ proliferative respon- Cambridge, MA, USA) for 6 days before 3H-thymidine siveness to the cytokines. was added and nuclear radioactivity assayed 18 hours later.11,12 Design and Methods Analysis of AML colony formation. AML cells (106 cells/mL) were cultured in suspension cultures in growth factor-con- AML cells taining medium alone or medium with additional exoge- The study was approved by the local Ethics Committee nous chemokines for 7 days before 100 µL of the cell sus- (Regional Ethics Committee III, University of Bergen, pension were mixed with 900 µL of methylcellulose medi- Norway) and samples were collected after informed con- um containing erythropoietin, GM-CSF, SCF and IL3 sent. The study included 68 consecutive adult patients (31 (MethoCult H4434; Stem Cell Technologies).11,12 The AML females and 37 males; median age 64 years and range 29- blasts were thereafter cultured (Costar 3524 24-well cul- 82 years) with high peripheral blood blast counts ture plates, 0.5 ml medium per well) for 14 days before (>7×109/L).11,12 AML cells were isolated by density gradient colony numbers were determined by light microscopy. separation and included at least 95% leukemic blasts.11-14 A Chemokine release assay. AML blasts (2×106 cells in 2 mL) more detailed characterization of the patients is given in were cultured in 24 well culture plates (Costar 3524 cul- the online supplementary section. ture plates) for 48 hours before chemokine levels were determined by Quantikine enzyme linked immunosor- Flow cytometric analysis of chemokine receptors and bent assays (ELISA) from R&D Systems, except the NFκB subunits CXCL4 analysis (CoaChrome; Wien, Austria). The mini- The expression of chemokine receptors and NFκB sub- mal detection limits are included in Table 1. haematologica/the hematology journal | 2007; 92(03) | 333 | O. Bruserud et al. Table 1. Chemokine release by native human AML cells derived from 68 consecutive patients. Patients with detectable chemokine release Chemokine Detection Number Median Range limit of concentration (pg/mL) (pg/mL) patients (pg/mL) CCL1 4 43 617 6.1->1000 CCL2 5 59 1720 7.3-5722 CCL3 75 53 5209 102-13,836 CCL4 150 53 2902 151-26,420 CCL5 1.2 67 236 2.0-2288 CCL7 27 40 751 42-935 CCL11* 5 0 −− CCL13 5 45 47.4 5.4-238 CCL17 11 31 114 11.7-3704 CCL20 4.5 49 128 4.7-1393 CCL21* 20 0 −− CCL22 260 41 1088 263->40,00 CCL23 9 28 19.8 12.9-23.3 CCL24 13 39 394 15.2-5080 CCL25* 26 0 −− CCL26* 4.5 15 13.1 5.1-82.8 CCL27* 3 0 −− CCL28* 7 14 7.8 7.1-41.7 CXCL1 60 50 7196 67-13,610 CXCL4 0.05 59 0.34 0.05-8.7 CXCL5 40 42 1067 41->20,000 CXCL6 3.2 30 53.9 4.2-2328 CXCL8 30 64 22,720 42-33,720 CXCL9 60 30 822 78-15,815 CXCL10 60 48 1782 64.2-24,906 CXCL11 40 28 168 40.7-3980 CXCL12* 18 10 37.5 28.5-623 CXCL13 3.5 38 189 3.5-1303 Native human AML cells were cultured for 48 hours and chemokine levels determined in the supernatants by ELISA.
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