Submitted May 21, 2008
Accepted February 7, 2009
NF1 haploinsufficiency and ICSBP-deficiency synergize in the development of leukemias
Jessica Koenigsmann, Cornelia Rudolph, Sandrine Sander, Olivia Kershaw, Achim D. Gruber, Lars Bullinger, Brigitte Schlegelberger, and Dirk Carstanjen*
Leibniz-Institut fuer Molekulare Pharmakologie, Berlin, Germany
Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany
Department of Physiological Chemistry, University of Ulm, Ulm, Germany
Department of Veterinary Pathology, Freie Universitaet Berlin, Berlin, Germany
Department of Internal Medicine III, University of Ulm, Ulm, Germany
* Corresponding author; email: carstanjen{at}fmp-berlin.de.
Loss of neurofibromin or Icsbp both lead to a myeloproliferative disorder (MPD). Transcription of NF1 is directly controlled by ICSBP. It has been postulated that loss of NF1-expression due to loss of transcriptional activation by ICSBP contributes to human hematological malignancies. To investigate the functional cooperation of these two proteins we have established Icsbp-deficient mice with Nf1-haploinsufficiency. We here demonstrate that loss of Icsbp and Nf1-haploinsufficiency synergize to induce a forced myeloproliferation in Icsbp-deficient mice due to an expansion of a mature myeloid progenitor cell. Furthermore, Nf1-haploinsufficiency and loss of Icsbp contribute synergistically to progression of the MPD towards transplantable leukemias. Leukemias are characterized by distinct phenotypes, which correlate with progressive genetic abnormalities. Loss of Nf1-heterozygosity is not mandatory for disease progression, but its occurrence with other genetic abnormalities indicates progressive genetic alterations in a defined subset of leukemias. These data show that loss of the two tumor suppressor genes Nf1 and Icsbp synergize in the induction of leukemias.
