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Expression of TGF-β receptor ALK-5 has a negative impact on outcome of patients with acute myeloid leukemia

Leukemia volume 25, pages 375–379 (2011)Cite this article

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The transforming growth factor (TGF)-β superfamily has been implicated into different physiological and pathological processes in a broad range of cell systems, including fibroblasts, immune, stem, endothelial, mural and tumor cells. With three TGF-β isoforms, three activin isoforms and over 20 bone morphogenic proteins (BMPs), the TGF-β superfamily represents a complex signaling pathway. The TGF-β receptor complex is composed of type I, type II and accessory receptors. There are seven isoforms of type I receptors termed activin receptor-like kinases (ALKs) 1–7. Targeted inactivation of TGF-β signaling components in mice revealed the pathway's crucial role in vascular morphogenesis as animals lacking various TGF-β superfamily members die at mid-gestation during embryogenesis because of defects in vascular development. In humans, dysregulation of the pathway is responsible for a broad range of diseases, including vascular diseases, hereditary cancer syndromes and the autosomal-dominant disorder Hereditary Hemorrhagic Teleangiectasia (also named Rendu-Osler-Weber syndrome). In leukemia, the role of TGF-β has been infrequently studied. It has been reported to either stimulate the growth of leukemic blasts in vitro or to reduce blast cell proliferation, thereby rendering them insensitive to chemotherapy (reviewed in Otten et al.1).

In acute myeloid leukemia, bone marrow neoangiogenesis has an important pathogenetic role. Increased microvessel density in bone marrow sections from acute myeloid leukemia (AML) patients compared with those patients with reactive disorders has been found. This increase of endothelial cells is accomplished by enhanced production of angiogenic growth factors. Secondly, hematopoietic and endothelial cells are derived from a common precursor, the hemangioblast. Therefore, many surface antigens are shared between both cell types such as CD34 or receptors for vascular endothelial growth factor (VEGF) (reviewed in Ayala et al.2). Hence, we reasoned that the TGF-β superfamily receptors ALK-1 and ALK-5, which have an important role in endothelial cells (EC) behavior, might be involved in the pathogenesis of AML.

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Acknowledgements

We thank Dr R Schlenk, University Hospital Ulm, Germany for providing clinical data of study patients, and the members of the Center for Transfusion Medicine of the University Hospital Hamburg-Eppendorf for providing the buffy coats of healthy donors, which were used for isolation of OECs. This work was supported in part by the ‘Eppendorfer Krebs- und Leukämiestiftung’.

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  1. J Otten and L Schmitz: These authors contributed equally to the work.

Authors and Affiliations

  1. Department of Oncology and Hematology with sections Pneumonology and Bone Marrow Transplantation, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    J Otten, L Schmitz, A Schultze, S Loges, C Bokemeyer & W Fiedler

  2. Department of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    E Vettorazzi

  3. Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    A H Marx, R Simon & G Sauter

  4. Department of Hematology, Hemostasiology, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany

    J Krauter

  5. Institute for Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    S Loges

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  1. J Otten
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Correspondence to W Fiedler.

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Otten, J., Schmitz, L., Vettorazzi, E. et al. Expression of TGF-β receptor ALK-5 has a negative impact on outcome of patients with acute myeloid leukemia. Leukemia 25, 375–379 (2011). https://doi.org/10.1038/leu.2010.273

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