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Thrombopoietin Supports the Continuous Growth of Cytokine-Dependent Human Leukemia Cell Lines HG Drexler, M Zaborski and H Quentmeier

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Thrombopoietin Supports the Continuous Growth of Cytokine-Dependent Human Leukemia Cell Lines HG Drexler, M Zaborski and H Quentmeier Leukemia (1997) 11, 541–551 1997 Stockton Press All rights reserved 0887-6924/97 $12.00 Thrombopoietin supports the continuous growth of cytokine-dependent human leukemia cell lines HG Drexler, M Zaborski and H Quentmeier DSMZ-German Collection of Microorganisms and Cell Cultures, Department of Human and Animal Cell Cultures, Mascheroder Weg 1 B, D-38124 Braunschweig, Germany Hematopoiesis is a complex process of regulated cellular pro- nate membrane receptor. This binding triggers a series of intra- liferation and differentiation from the primitive stem cells to the cellular mediators involved in the growth factor’s signaling final fully differentiated cell. The long and extensive search for a factor specifically regulating megakaryocytopoiesis led to the pathways. Recently, a novel hematopoietic growth factor, cloning of a hormone, here called thrombopoietin (TPO), that termed thrombopoietin (TPO), was cloned and shown to be a specifically promotes proliferation and differentiation of the megakaryocytic lineage-associated growth and differentiation megakaryocytic lineage. The availability of recombinant TPO factor. Binding of TPO to its receptor, c-MPL, mediates plei- and its imminent clinical use has made a more detailed under- otropic effects on megakaryocyte development in vitro and in standing of its effects on hematopoietic cells more urgent. Nor- vivo. TPO is clearly the primary regulator of this cell lineage mal megakaryocyto- and thrombopoiesis occurs predomi- nantly in the bone marrow, a difficult organ to study in situ, acting at all levels of megakaryocytopoiesis and thrombopo- particularly in humans, due to the low numbers of megakary- iesis (reviewed in Ref. 1). ocytic progenitors and the consequent difficult isolation as The availability of TPO will be of considerable clinical pure populations. Thus, we developed an in vitro system which importance for the treatment of thrombocytopenias following may allow us to address questions regarding the biology of high-dose chemotherapy (of solid tumors and hematological TPO. The acute myeloid leukemia (AML)-derived cell lines HU- malignancies), irradiation (for instance, in the context of bone 3, M-07e, M-MOK and TF-1 have absolute dependence on gra- marrow transplantation) and other bone marrow failures (eg nulocyte–macrophage colony-stimulating factor (GM-CSF). We 2 cultured these cells long term (.6 months) in the continuous due to myelodysplastic syndromes, aplastic anemias). Still, presence of TPO (omitting GM-CSF). TPO alone supported the while TPO has moved tremendously quickly from theory to maintenance and expansion of these sister cell lines, HU- clinical trials in just about 2 years, more insight into the physi- 3/TPO, M-07e/TPO, M-MOK/TPO and TF-1/TPO, that displayed ology and pathophysiology of TPO, its effects and its regu- somewhat longer doubling times, a larger cell size, and a higher lation, is clearly required. To that end, it is absolutely essential percentage of polynucleated giant cells and slightly adherent cells than the corresponding countercultures grown with GM- that both in vivo and in vitro TPO research will be performed. CSF. In the absence of TPO the cells died quickly, within a few Studies on megakaryocytopoiesis using bone marrow speci- days; thus, the TPO-grown cell lines have an absolute depen- mens are hampered by the paucity of megakaryocytic pro- dence on this factor, but could all be switched back to growth genitors and more committed cells within the total population with GM-CSF. In comparison with the GM-CSF-treated cells, the (requiring sophisticated purification steps) and the striking het- receptors for GM-CSF and interleukin-3 (IL-3) were down-regu- erogeneity of the bystander cells. Continuous cell lines, usu- lated and the receptors for stem cell factor (SCF) and TPO were up-regulated in the TPO-exposed cells. A short-term prolifer- ally derived from leukemias involving this cell lineage, rep- ation assay showed a stronger response of the TPO-cell lines resent excellent alternative in vitro models due to their to erythropoietin, GM-CSF, IL-3, PIXY-321, SCF and TPO than monoclonal homogeneity and unlimited availability. How- the GM-CSF-cell lines. Flow cytometric analysis of the GM-CSF- ever, only a few cell lines appear to respond to TPO, at least and TPO-cultured lines displayed an up-regulation of the in terms of enhanced proliferation or induced differen- megakaryocytic surface markers CD41, CD42 and CD61, and a tiation.1,3 In order to facilitate future investigations in TPO, down-regulation of the erythroid marker glycophorin A in the latter cell lines, suggesting some differentiation along the we attempted to establish and characterize cell lines that are megakaryocytic lineage. Thus, in long-term exposure, TPO absolutely dependent on TPO for growth and survival. These appears to have both a proliferative and a differentiative effect TPO-dependent cell lines provide an experimental setting in on responsive cells. Under serum-deprived culture conditions, which the study of TPO regulation and its effects can be TPO acted as a survival factor on the TPO-cell lines. Taken adequately performed. Furthermore, AML M7-derived cell together, these findings indicate that the TPO-dependent cell lines as in vitro systems of human megakaryocytes will con- lines represent important biological reagents for further characterization of the biology of TPO and should also provide tinue to be useful for the evaluation of any aspect of megakar- a great aid for future in vitro experiments aimed at elucidating yocyto- and thrombopoiesis. megakaryocyto- and thrombopoiesis. Keywords: leukemia; cell lines; TPO; cytokines Materials and methods Introduction Leukemia cell lines Regulation of blood cell production, differentiation, and cer- The continuous cell lines were taken from the stock of the cell tain functional responses is mediated in part by specific hema- bank of the DSMZ (German Collection of Microorganisms and topoietic growth factors (or cytokines). The initial event in Cell Cultures)4,5 or were generously provided by the investi- growth factor action consists of the factor’s binding to its cog- gators who established the cell lines for research purposes (Table 1): HU-3 (kindly provided by Dr D Morgan, Philadel- phia, PA, USA);6,14 M-07e (DSM ACC 104);7 MB-02 (Dr D Correspondence: HG Drexler Morgan);8 M-MOK (Dr T Kudo, Sendai, Japan);9 MUTZ-2 Received 23 October 1996; accepted 17 December 1996 (DSM ACC 271);10 MUTZ-3 (DSM ACC 295);10 OCI-AML-1 TPO-dependent leukemia cell lines HG Drexler et al 542 Table 1 Leukemia cell lines used Cell line Ref. Phenotype of cell linea Year of Original Tissue of Age/Sex 48 h Incubation with establishment diseaseb originb (patient) proliferative reagents during response to cytokine switchingd TPOc HU-3 6 megakaryocytic/erythroid 1991 AML M7 BM 69 F 11.4 GM-CSF vs TPO M-07e 7 megakaryocytic 1987 AML M7 BM 0.5 F 8.4 5637 CM vs TPO MB-02 8 megakaryocytic/erythroid 1986 AML M7 PB 70 M 1.1 GM-CSF vs TPO M-MOK 9 megakaryocytic 1989 AML M7 BM 1 F 11.0 GM-CSF vs TPO MUTZ-2 10 myeloid 1993 AML M2 PB 62 M 1.5 SCF vs TPO MUTZ-3 10 monocytic 1993 AML M4 PB 29 M 2.2 5637 CM vs TPO OCI-AML-1 11 myeloid 1987 AML M4 PB 73 F 3.1 5637 CM vs TPO OCI-AML-5 11 myeloid 1990 AML M4 PB 77 M 1.5 5637 CM vs TPO TF-1 12 erythroid 1987 AML M6 BM 37 M 14.5 5637 CM vs TPO UT-7 13 megakaryocytic/pluripotent 1988 AML M7 BM 64 M 1.4 GM-CSF vs TPO aPhenotype of the cell lines based on the expression of immunological surface markers, capability to differentiate upon stimulation, functional features, etc. bAs described in the original publication on the respective cell line: AML: acute myeloid leukemia (with the morphological subtypes of M2 for myeloblastic, M4 for myelomonocytic, M6 for erythroid and M7 for megakaryocytic); BM: bone marrow; PB: peripheral blood. cCells were extensively washed and then incubated in the absence or presence of 100 U/ml TPO for 48 h; 3H-thymidine was added for the last 4 h of incubation; 3H-thymidine incorporation was determined by standard b scintillation counting; stimulation indices (SI) refer to the untreated control culture; an SI .2 is considered to be significant. dThe cytokines were used at the following concentrations: GM-CSF (5 ng/ml); SCF (50 ng/ml); TPO (20 ng/ml); 5637 CM (10% vol). (Dr EA McCulloch, Toronto, Canada);11 OCI-AML-5 (DSM 10 cell lines were washed, divided into two aliquots (starting ACC 247);11 TF-1 (DSM ACC 334);12 UT-7 (Dr M Souyri, Paris, concentration of 0.5 × 106 cells/ml in 1 ml) and incubated in France).13 They were grown at 37°C in a humidified atmos- medium containing one of the following cytokines or CM: phere of air containing 5% CO2. The basal growth media 5637 CM (at 10% vol); GM-CSF (at 5 ng/ml; kindly provided (RPMI 1640 or alpha-MEM; Gibco BRL, Eggenstein, Germany) by Dr A Mire-Sluis, London, UK); SCF (at 50 ng/ml; kindly were supplemented with 5–20% heat-inactivated (at 56°C for provided by Dr A Mire-Sluis); or TPO (at 20 ng/ml; kindly pro- 45 min) fetal bovine serum (FBS) (Sigma, Deisenhofen, vided by Amgen, Thousand Oaks, CA, USA). The optimal con- Germany). For selective experiments, cells were incubated in centration of each cytokine was determined empirically by the serum-free medium (Macrophage-SFM Medium; Gibco BRL). 3H-thymidine uptake as outlined below. During the first week, Freedom of mycoplasma contamination was determined after the cells were weaned off the initially added cytokine by pro- thawing the cell lines by cultivation on agar and by frequent gressively decreasing the concentrations of this reagent while DAPI staining.15 Cultures were passaged according to stan- simultaneously adding and increasing daily the new cytokine.
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