Erythropoiesis Regulatory Proteins and Cytokines in Acute Leukemia Patients

Erythropoiesis regulatory proteins – erythropoietin (EPO), hypoxia-inducible factor (HIF-1α), proteins involved in iron metabolism - ferritin, hepcidin (HP), in collaboration with cytokines (IL-2, IL-6 and TNF-α) take part in hematopoietic regulation, in stress response, in apoptosis and are generally involved in the pathogenetic pathways in acute leukemias (AL). We suggested that the existing disbalance in the level of these proteins in (AL) at the time of diagnosis might contribute to the clinical course of the disease (anemia, fever, hypoxia, organomegaly, tumor load) and may be modified by the chemotherapy.

To reveal changes in the level of regulatory proteins and major interleukins in serum we measured their concentrations in AL patients at different time points: at diagnosis, during the course of chemotherapy (day∼+3-7), at time of WBC nadir after chemotherapy (day∼+14-15), and time of complete remission. We also detected the level of ferritin, HP, HIF-1α and interleukins in homogenates of blast cells in order to reveal the discrepancies in serum and cellular concentrations of these proteins.

We have studied 87 newly diagnosed AL patients. All patients were tested for serum ferritin (SF) by immunoradiometric method; HIF-1α, HP by immunoenzyme method in “the sandwich” version in serum; EPO, IL-2, IL-6 and TNF-α by IFA method. Ferritin, HP, HIF-1α and interleukins were also determined in homogenates blast cells.

The data of our measurements are reflected in the table.

The values of basic regulatory proteins in serum of AL patients were high already at diagnosis. SF was increased in all patients and its high level was detected through the whole study. In spite of Hb decrease and hypoxia in AL patients the values of HP and HIF-1α are increased due to active proliferation and antiinflammatory processes. It has to be emphasized that high values of HIF-1α in serum have been revealed at time of agranulocytosis (23,7±4,1 pg/ml). High serum values of most important pro-inflammatory cytokine IL-6 (78,4±19,4 pg/ml) and very low values of anti-inflammatory IL-2 (96,2±14,8 pg/ml) were found at diagnosis. Despite low serum concentration, we discovered a high level of TNF-α (179,84±28,3 pg/ml) in homogenates of blast cells. IL-6 level of 1392,7±275,2 pg/m detected in blast cells, 17-fold times exceeded its serum concentration. Value of IL-2 in blast cells remained low at diagnosis as well as at +3-7 days of intensive chemotherapy (115,5±36,5 and 146,4±30,1 pg/ml, respectively). High values of HP and HIF-1α in blast cells were fixed during chemotherapy. HIF-1α concentration has been elevated 15-fold at +3-7 days (85,8 ±24,5 pg/ml). We focus on the fact that there have been high meanings of all parameters studied (SF, EPO, HIF-1α, HP) in complete remission.

So our findings indicate the severe discordance in regulatory proteins expression levels in serum and blast cells comparing to donors serum and leukocytes levels.

1. Our study has shown that iron metabolic proteins are integrated in the regulative mechanisms of tumor pathogenesis.

2. The observed changes in the main interleukins levels revealed the severe disbalance in interleukin network in particular regarding the expression in blast cells.

No relevant conflicts of interest to declare.