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Cytokines increase theraputic specificity index

TGFβ-induced SMAD2 phosphorylation predicts inhibition of thymidine incorporation in CD34+ cells from healthy donors, but not from patients with AML after MDS

Leukemia volume 15, pages 942–949 (2001)Cite this article

Abstract

Cells from patients with MDS-derived AML display heterogeneous proliferative responses to transforming growth factor beta (TGFβ). We analyzed growth inhibition and SMAD2 phosphorylation by TGFβ in CD34+ cells from nine patients, as compared to normal controls. While TGFβ consistently inhibited thymidine incorporation of normal cells (41% of control, P < 0.05), cells from patients with aml were growth-inhibited in only four of seven cases (40%), whereas TGFβ stimulated thymidine incorporation in the three other samples (166%). Remarkably, TPO reverted the stimulatory effect of TGFβ to profound growth inhibition. Upon exposure to TGFβ, SMAD2 protein was phosphorylated in normal CD34+ cells (n = 3), CD34+ leukemic blasts from all examined patients with AML (n = 4), and in the myeloid leukemic cell lines M-07e and HEL. TGFβ inhibited TPO-mediated thymidine incorporation, cell proliferation and survival in all samples analyzed. In M-07e cells and CD34+ cells from healthy donors, this inhibition was enhanced by an antagonist of JAK2 (AG490), but not a MEK-1 antagonist (PD098059). Conversely, in CD34+ cells from a patient with AML, both AG490 and PD098059 significantly enhanced TGFβ-mediated suppression of TPO-induced thymidine incorporation. Thus, in MDS-derived AML, altered responses to TGFβ may be due to defects downstream of SMAD2 and may involve MAPK activation.

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Acknowledgements

This work was supported by the Schaufler-Foundation, Frankfurt/Main, Germany and the Deutsche Knochenmarkspenderdatei (DKMS). We thank Dr JL Nichol (Amgen Inc, Thousand Oaks, CA, USA) for providing recombinant human MGDF.

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  1. W-K Hofmann

    Present address: Department of Hematology and Oncology, Cedars Sinai Medical Center, UCLA, Los Angeles, CA 90048, USA

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  1. Division of Hematology, Department of Internal Medicine III, Johann Wolfgang Goethe University, Frankfurt, Germany

    S Koschmieder, W-K Hofmann, J Kunert, S Wagner, K Ballas, G Seipelt, D Hoelzer, OG Ottmann & U Kalina

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Koschmieder, S., Hofmann, WK., Kunert, J. et al. TGFβ-induced SMAD2 phosphorylation predicts inhibition of thymidine incorporation in CD34+ cells from healthy donors, but not from patients with AML after MDS. Leukemia 15, 942–949 (2001). https://doi.org/10.1038/sj.leu.2402119

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