Die Rolle des Hedgehog - Signalweges in der AML

Hochschulschrift

Zusammenfassung: Hedgehog (HH) signaling was shown to be essential for the maintenance of leukemic stem cells in BCR-ABL+ myeloid leukemia, while regular hematopoietic stem cells are independent of HH-signaling. The aim of the presented study was to investigate the role of hedgehog signaling in AML.Results: Immunohistochemistry stainings for the downstream target and transcription factor of the HH-signaling pathway GLI1 demonstrated elevated expression indicating pathway activation in 84% of primary AMLs (n=40) and in all cases of MDS (n=4), while GLI1 expression was absent/low in bone marrow of healthy donors (n=5). Also other pathway members like the Smoothened (SMO)-receptor (55%) and the activating HH-ligands SHH/IHH (36%) were upregulated in AML. Pharmacological inactivation of the SMO-receptor with Cyclopamine and LDE225 (Novartis) in primary AML samples (n=20) induced apoptosis and reduced proliferation in 45% of the examined samples. The responsive AMLs also showed reduced colony forming ability after SMO-inhibiton, indicating a loss of the leukemic progenitor population, while 55% of the samples were completely resistant to SMO-inhibition. Responsiveness to SMO-inhibitors was not correlated with Flt3 mutational status, presence of MLL-fusion oncogenes or certain chromosomal aberrations. In contrast, 89% of the patients that were responsive to SMO-inhibition had a normal karyotype. Furthermore, AML patients that showed the strongest response to SMO-inhibition in vitro had a significantly shorter survival time than non-responders, which might indicate activation of HH-signaling as an adverse prognostic factor in AML.Cotransfection of GLI-LUC reporter constructs and AML gene fusions indicated direct pathway activation of AML1-ETO, TEL-TRKC, TEL-PDGFR and JAK V617F (PV).Conclusion: Thus we conclude that the Hh pathway is activated in subtypes of human AML and represents an interesting target for treatment of certain patient populations, especially patients with normal karyotype

Angaben zum Objekt

• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Sprache: Deutsch
• Anmerkungen: Albert-Ludwigs-Universität Freiburg, Dissertation, 2015

Klassifikation und Themen

• Schlagwort: Hedgehog ; Leukämie ; Akute myeloische Leukämie ; Hedgehog ; Krebs ; Onkologie

Beteiligte, Orts- und Zeitangaben

• Ereignis: Veröffentlichung
• (wo): Freiburg
• (wer): Universität
• (wann): 2015
• Urheber: Landwerlin, Klemens
• Beteiligte Personen und Organisationen: Dierks, Christine

Weitere Informationen

• DOI: 10.6094/UNIFR/10296
• URN: urn:nbn:de:bsz:25-freidok-102961
• Rechteinformation: Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Letzte Aktualisierung: 25.03.2025, 13:53 MEZ