gms | German Medical Science

27. Deutscher Krebskongress

Deutsche Krebsgesellschaft e. V.

22. - 26.03.2006, Berlin

The AML1-ETO Fusion Gene and the FLT3 Length Mutation Collaborate in Inducing Acute Leukemia in a Murine Bone Marrow Transplantation Model

Meeting Abstract

  • corresponding author presenting/speaker Christina Scheßl - Med.Klinik III, Klinikum Großhadern, München, Deutschland
  • Vijay P. S. Rawat - Med.Klinik III, Klinikum Großhadern, München
  • Monica Cusan - Med.Klinik III, Klinikum Großhadern, München
  • Aniruddha Deshpande - Med.Klinik III, Klinikum Großhadern, München
  • Tobias M. Kohl - Med.Klinik III, Klinikum Großhadern, München
  • Patricia M. Rosten - The Terry Fox Laboratory, BC Cancer Agency, Vancouver, Canada
  • Karsten Spiekermann - Med.Klinik III, Klinikum Großhadern, München
  • R. Keith Humphries - The Terry Fox Laboratory, BC Cancer Agency, Vancouver, Canada
  • Susanne Schnittger - Med.Klinik III, Klinikum Großhadern, München
  • Wolfgang Kern - Med.Klinik III, Klinikum Großhadern, München
  • Wolfgang Hiddemann - Med.Klinik III, Klinikum Großhadern, München
  • L. Quintanilla-Martinez - GSF, Institut für Pathologie, Neuherberg

27. Deutscher Krebskongress. Berlin, 22.-26.03.2006. Düsseldorf, Köln: German Medical Science; 2006. DocOP103

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter: http://www.egms.de/de/meetings/dkk2006/06dkk213.shtml

Veröffentlicht: 20. März 2006

© 2006 Scheßl et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielf&aauml;ltigt, verbreitet und &oauml;ffentlich zug&aauml;nglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

Experimental data show that two of the most frequent genetic alterations in AML, the AML1-ETO (A/E) fusion gene and the FLT3 length mutation (FLT3-LM) are mostly insufficient to induce leukemia on their own. These findings support the thesis that collaboration of two classes of genetic alterations, altering proliferation or differentiation, is necessary for leukemogenesis. 135 patients with A/E positive AML were analysed and additional mutations affecting signal transduction were found in 38 % of all cases (FLT3-LM 10.3 %, KIT 8.1 % and NRAS 9.6 %). In contrast, none of the patients showed alterations associated with transcriptional regulation such as MLL-PTD. To test the hypothesis that A/E collaborates with FLT3-LM in inducing acute leukemia, we transplanted mice with bone marrow (BM) cells expressing A/E, FLT3-LM or both alterations. Mice transplanted with BM cells expressing A/E or FLT3-LM alone did not develop any disease. In contrast, mice (n=11) transplanted with BM cells expressing both mutations died of an aggressive acute leukemia. The developing leukemias differed in their phenotype: 7 animals developed AML and 4 animals displayed ALL. Furthermore, the majority of AML cases showed simultaneous expression of lymphoid antigens as described in patients with A/E positive AML. Our experiments further show, that the collaboration of A/E with FLT3-LM was depending on DNA binding activity of the fusion gene as well as on the kinase activity of the FLT3-LM in a CFU-S assay. Treatment of cells co-infected with A/E and FLT3-LM with the kinase inhibitor PKC412 resulted in a 62 % reduction of the CFU-S frequency. To further explore a possible contribution of retroviral insertional mutagenesis to the transformation process in this model, 10 retroviral integration sites were subcloned and sequenced from 4 leukemic mice: all 10 sites were unique with no indication of a common integration site associated with the leukemic transformation. These data provide direct functional evidence for the oncogenic collaboration between A/E with a class of activating mutations, recurrently found in patients with t(8;21), and add experimental data to the clinical observation which demonstrated a significant inferior treatment outcome in patients with AML1-ETO and additional mutations of receptor tyrosine kinases.