Use of human leukemia-lymphoma cell lines in hematological research: effects of thrombopoietin on human leukemia cell lines.

Normal and malignant hematopoiesis (including megakaryocytopoiesis and thrombopoiesis) is regulated by a family of glycoproteins, the hematopoietic growth factors (cytokines). The identification of the orphan cytokine receptor MPL led to the cloning of the primary regulator of platelet production, termed thrombopoietin (TPO). TPO promotes both the proliferation of megakaryocytic progenitor cells and their differentiation into platelet-producing megakaryocytes. Expression and function of this new cytokine ligand-receptor pair were also examined in primary and cultured leukemia cells. Among the large panel of human leukemia cell lines studied, MPL expression occurred predominantly in lines with erythro-megakaryocytic phenotypes. The MPL receptor was also found in a large percentage of primary acute myeloid leukemia (AML) cases. MPL expression was not limited to certain morphological subtypes, although the highest percentages were seen in the erythroid and megakaryocytic subclasses. A significant portion of AML cases and of erythroid, megakaryocytic and myeloid leukemia cell lines co-expressed TPO and MPL and mRNA transcripts, although no biologically active TPO appeared to be secreted by these cells. Recombinant TPO induced clearly in vitro proliferation of a significant percentage of primary AML cases, predominantly of the megakaryocytic subtype. TPO significantly enhanced the cytokine-induced growth of AML cells in a substantial fraction of cases responsive to GM-CSF, IL-3, or SCF. While none of 30 growth factor-independent erythro-megakaryocytic leukemia cell lines responded to TPO with increased proliferation, TPO strongly augmented the growth of several constitutively cytokine-dependent cell lines (HU-3, M-07e, M-MOK, OCI-AML-1, TF-1) which can be made TPO-dependent and used as bioassays. Neither in primary cells nor in cell lines did TPO appear to induce morphological, functional or immunological differentiation. Expression of the MPL receptor is not correlated with a proliferative response to TPO. The data reviewed here document the wide expression of the MPL receptor on myeloid leukemia cells and also suggest some proliferative effects on certain leukemia cells, apparently on non-megakaryocytic leukemia cells as well TPO-responsive cell lines represent powerful tools for further (patho-)physiological analyses.