Thrombopoietin and interleukin 11 have different modulatory effects on cell cycle and programmed cell death in primary acute myeloid leukemia cells

The c-mpl ligand, thrombopoietin (TPO), is a physiologic regulator of plate let and megakaryocytic production, acting synergistically on thrombopoiesis with the growth factors interleukin 11 (IL-11), stem cell factor, interleu kin 3 (IL-3), interleukin 6 (IL-6), and granulocyte-macrophage colony-stimu lating factor. Because some of these growth factors, especially TPO and IL- 11, are now being evaluated clinically to reduce chemotherapy-associated th rombocytopenia in cancer patients, we evaluated 25 acute myeloid leukemia ( AML) samples to test whether TPO, IL-11, and other early-acting megakaryocy te growth factors can affect leukemic cell proliferation, cell cycle activa tion, and programmed cell death (PCD) protection. TPO induced proliferation in the majority of AML samples from an overall mean proportion of S-phase cells of 7.8% +/- 1.5% to 14.5% +/- 2.1% (p = 0.0006). Concurrent Go cell d epletion was found in 47.3% of AML samples. TPO-supported leukemic cell pre cursor (CFU-L) proliferation was reported in 5 of 17 (29.4%) of the samples with a mean colony number of 21.4 +/- 9.6 x 10(5) cells plated. In 13 of 1 9 samples, a significant protection from PCD (from an overall mean value of 13% +/- 0.7% to 8.8% +/- 1.8%; p = 0.05) was detected after TPO exposure. Conversely, IL-ll-induced cell cycle changes (recruitment from G(0) to S ph ase) were detected in only 2 of 14 samples (14.2%). In addition, IL-ll show ed little, if any, effect on CFU-L growth (mean colony number = 17.5 9.5) o r apoptosis. Combination of TPO with IL-11 resulted in only a slight increa se in the number of CFU-L, whereas IL-3 and stem cell factor significantly raised the mean colony numbers up to 119.2 +/- 68.3 and 52.9 +/- 22.1 X 105 cells plated, respectively. We conclude that TPO induces cell cycle activa tion in a significant proportion of cases and generally protects the majori ty of AML blast cells from PCD. On the other hand, IL-11 has little effect on the cell cycle or PCD. Combination of bath TPO and IL-11 is rarely syner gistic in stimulating AML clonogenic growth. These findings may be useful f or designing clinical studies aimed at reducing chemotherapy-associated thr ombocytopenia in AML patients. (C) 1999 International Society for Experimen tal Hematology. Published by Elsevier Science Inc.