Growth response of acute myeloblastic leukemia cells to recombinant human thrombopoietin

Abstract

Thrombopoietin (TPO) is a newly identified hematopoietic growth factor that stimulates both megakaryopoiesis and thrombopoiesis through its interaction with a specific cell surface receptor encoded by the c-mpl proto-oncogene. In an effort to investigate the effect of TPO on human myeloid leukemia cells, the expression of c-mpl and the proliferative response to recombinant human (rh) TPO were investigated in a series of patients with acute myeloblastic leukemia (AML). Of 50 cases of AML, the c-mpl mRNA was detectable by means of Northern blot analysis in 26 cases, and the in vitro treatment with rhTPO led to proliferation of AML cells in 22 cases. The c-mpl expression and proliferative response to rhTPO was observed in all subtypes of AML and did not correlate with French-American-British classification, whereas all cases of M7-type AML cells expressed c-mpl and proliferated in response to rhTPO. Furthermore, rhTPO-induced proliferation of AML cells was augmented with the addition of interleukin-3 (IL-3), IL-6, stem cell factor, or granulocyte-macrophage colony-stimulating factor. These results suggested that c-mpl may be functional in terms of supporting proliferation of various types of AML cells and that TPO may contribute, at least in part, to abnormal growth of the cells, especially in combination with other hematopoietic growth factors.

Effects of thrombopoietin (c‐mpl ligand) on growth of blast cells from patients with transient abnormal myelopoiesis and acute myeloblastic leukemia

“…Expression of c-mpl is restricted to human hematopoietic cells such as megakaryocytes, platelets, CD34+ cells, human AML cells and blasts from myelodysplastic syndrome. In cells from patients with AML, detection of c-mpl mRNA has been reported to have an incidence of 52% (27) or 55% (26). In the present study, 4 of 11 AML case (36%) showed c-mpl mRNA.…”

“…Quadruplicate aliquots of cells (5x104 cells in 200ml RPMI supplemented with 10% FCS) were cultured in 96-well flat-bottom microtiter plates for 72 h at 37°C in the presence or absence of growth factors. The concentrations value was lower than 0.05 we considered that the proliferative response was significant as previously described (27). We performed morphological analysis of samples before and after stimulation of TPO and certified that proliferating cells were leukemic cells.…”

“…Many investigators have shown that the deregulated expression of growth factors and/or growth factor receptors can induce the abnormal growth and differentiation of cells in human leukemias and myeloproliferative syndromes (23,25). In human hematopoietic malignancies, about half of acute myeloblastic leukemia (AML) samples express c-mpl message (26,27). The growth responses of AML cells to TPO have also been studied (27).…”

“…In human hematopoietic malignancies, about half of acute myeloblastic leukemia (AML) samples express c-mpl message (26,27). The growth responses of AML cells to TPO have also been studied (27). Except for cells classified as M7, growth response and expression of c-mpl were not correlated with specific FAB classification.…”

An erythroid and megakaryocytic common precursor cell line (B1647) expressing both c‐mpl and erythropoietin receptor (Epo‐R) proliferates and modifies globin chain synthesis in response to megakaryocyte growth and development factor (MGDF) but not to erythropoietin (Epo)

“…myeloid leukaemic cells grow in the presence of human TPO (Matsumura et al, 1995), and the receptor transcript has been evidenced in several myeloid leukaemic cell lines (Methia et al, 1993). Although TPO stimulates leukaemic cell proliferation, it fails to induce cell differentiation.…”