Tumor necrosis factor alpha (Tnf-α) Production by acute myeloid leukemic (Aml) Blasts results in impaired proliferation of normal hematopoietic progenitor cells (Hpc)

Abstract Previously, we demonstrated that the production of proteinases by normal myeloid precursor cells was responsible for impaired proliferation of normal HPC in the presence of hematopoietic growth factors (HGF) in a liquid serum free medium culture consisting of IMDM, human serum albumin, cholesterol, transferrin and insulin. Addition of the serine proteinase inhibitor α-1 PI restored the proliferation. However, AML blasts co-cultured with normal HPC in the presence of α-1 PI, using micro-membrane-transwells (poresize 0.45 μm) in the absence of cell-cell contact, were still capable of suppressing the proliferation of normal HPC up to 60 ± 7% (n=17). AML blasts from all FAB classifications, but most profoundly AML-M4 blasts released a factor capable of strong inhibition of normal HPC (87 ± 2% (n=4)). TNF-α has been shown to be produced in high amounts by AML blasts, has previously shown to have anti-proliferative features and is a mediator in the pathways of cellular apoptosis. Therefore, we studied the effect of anti-TNF-α for its ability to neutralize the inhibitory effect of AML cells on in vitro proliferation of normal HPC in these serum fee co-cultures. Addition of anti-TNF-a completely restored the proliferation of normal CD34 + HPC in response to HGF. In addition, anti-TNF-α increased the proliferation of the AML blasts int he presence of HGF by 166 ± 43% (n=18) independent of their FAB classification. These results may indicate that treatment with anti-TNF-antibodies may increase the proliferative capacity of residual normal HPC in patients with AML, but may also lead to increased proliferation of the leukemic cells.