Autocrine stimulation by erythropoietin and autonomous growth of human erythroid leukemic cells in vitro.

Abstract

Autonomous colony formation is a frequent event in erythroleukemia. In 13 cases of early erythroid leukemias, we investigated whether erythropoietin (Epo) autocrine stimulation was responsible for the growth factor autonomy. Epo transcripts were detected by Northern blotting in cells from one patient. These cells also expressed an Epo receptor (1,000 receptors per cell) with a 420-pM affinity and Epo was detected in the supernatant of cultured cells. In 8 of the 13 cases, Epo transcripts were revealed by the polymerase chain reaction ranging from 0.5 to 500 copies per cell. In situ hybridization proved that these Epo transcripts were present in the blast cells. No Epo gene abnormalities were detected by Southern blotting. In two cases, leukemic cells were grown in the presence of Epo-neutralizing antibodies or Epo antisense oligomers. In one case, the antibody significantly reduced autonomous growth. In contrast, the antibody had no effect in the second case in which blast cells transcribed the Epo gene at a low level. However, Epo antisense oligomers partially inhibited autonomous growth. This inhibition was reversed by addition of exogenous Epo. Overall, these results suggest that an extracellular or intracellular autocrine Epo stimulation occurs in some cases of erythroid malignancies.

Adding self-renewal in committed erythroid progenitors improves the biological relevance of a mathematical model of erythropoiesis

“…We could first try to see up to which extent we could use the same model with different parameters values for modelling the appearance of erythroleukemia. It has for example been shown that an autocrine EPO production occurred in human erythroleukemia (Mitjavila et al, 1991). In our model this can be modelled quite simply by modifying the value of β.…”

Coexpression of erythropoietin and erythropoietin receptor in sporadic clear cell renal cell carcinoma

“…The mutation in VHL gene in these cells may affect their further development or differentiation into mature cells. The retention of Epo and EpoR coexpression in these precursor cells may lead to cell proliferation via the autocrine stimulation 27 and become a critical pathogenetic step in tumor formation. Our results indicate that sporadic and VHL-associated CCRCCs not only share genetic and morphological features but also share the autocrine loop pathway of Epo/EpoR coexpression.…”

Constitutive activation of mitogen-activated protein kinase pathway in acute leukemia cells

“…It is fascinating to speculate that constitutively activated signal transduction pathway constitutively, can be a critical step in leukemogenesis. [34][35][36][37][38][39] We should also bear in mind that MAPKs may specifically phosphorylate and transactivate the transcription factors and that they may then regulate the tyrosine kinase, including receptor tyrosine kinases, might be…”