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Blood, 15 August 2007, Vol. 110, No. 4, pp. 1291-1300.
Prepublished online as a Blood First Edition Paper on May 7, 2007; DOI 10.1182/blood-2006-10-049783.
 Previous Article | Next Article 
Submitted October 2, 2006
Accepted April 22, 2007
Gene expression profiling identifies distinct subclasses of core binding factor acute myeloid leukemia
Lars Bullinger*, Frank G Rucker, Stephan Kurz, Juan Du, Claudia Scholl, Sandrine Sander, Andrea Corbacioglu, Claudio Lottaz, Jurgen Krauter, Stefan Frohling, Arnold Ganser, Richard F Schlenk, Konstanze Dohner, Jonathan R Pollack, and Hartmut Dohner
Department of Internal Medicine III, University of Ulm, Ulm, Germany
Department of Physiological Chemistry, University of Ulm, Ulm, Germany
Department for Computational Molecular Biology, Max-Planck-Institute for Molecular Genetics, Berlin, Germany
Department of Hematology, Hemostaseology and Oncology, Hannover Medical School, Hannover, Germany
Department of Pathology, Stanford University, Stanford, CT, United States
* Corresponding author; email: lars.bullinger{at}uniklinik-ulm.de.
Core binding factor (CBF) leukemias, characterized by either inv(16)/t(16;16) or t(8;21), constitute acute myeloid leukemia (AML) subgroups with favorable prognosis. However, there exists substantial biological and clinical heterogeneity within these cytogenetic groups, which is not fully reflected by the current classification system. To improve the molecular characterization we profiled gene expression in a large series (n=93) of AML patients with CBF leukemia [inv(16) n=55, t(8;21) n=38]. By unsupervised hierarchical clustering we were able to define a subgroup of CBF cases (n=35) characterized by shorter overall survival times (P=0.03). While there was no obvious correlation with fusion gene transcript levels, FLT3 tyrosine kinase domain, KIT, and NRAS mutations, the newly defined inv(16)/t(8;21)-subgroup was associated with elevated white blood cell counts and FLT3 internal tandem duplications (P=0.011 and P=0.026, respectively). Supervised analyses of gene expression suggested alternative cooperating pathways leading to transformation. In the "favorable" CBF leukemias anti-apoptotic mechanisms and deregulated mTOR-signaling, and in the newly defined "unfavorable" subgroup aberrant MAPKinase-signaling and chemotherapy-resistance mechanisms might play a role. While the leukemogenic relevance of these signatures remains to be validated, their existence nevertheless supports a prognostically relevant biological basis for the heterogeneity observed in CBF leukemia.
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