Nf haploinsufficiency and Icsbp deficiency synergize in the development of leukemias

摘要

Loss of neurofibromin or interferon consensus sequence binding protein (Icsbp) leads to a myeloproliterative disorder. Transcription of NF is directly controlled by ICSBP. It has been postulated that loss of NF expression resulting from loss of transcriptional activation by ICSBP contributes to human hematologic malignancies. To investigate the functional cooperation of these proteins, we have established Icsbp-deficient mice with Nfhaploinsufficiency. We here demonstrate that loss of Icsbp and Nf haploinsufficiency synergize to induce a forced my-eloproliferation in Icsbp-deficient mice because of an expansion of a mature myeloid progenitor cell. Furthermore, Nf haploinsufficiency and loss of Icsbp contribute synergistically to progression of the myeloprol iterative disorder toward transplantable leukemias. Leukemias are characterized by distinct phenotypes,which correlate with progressive genetic abnormalities. Loss of Nf heterozygos-ity 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 tumor suppressor genes Nf and Icsbp synergize in the induction of leukemias.