title: Nf1 haploinsufficiency and Icsbp deficiency synergize in the development of leukemias.
abstract: Loss of neurofibromin or interferon consensus sequence binding protein (Icsbp) leads to a myeloproliferative disorder. Transcription of NF1 is directly controlled by ICSBP. It has been postulated that loss of NF1 expression resulting from loss of transcriptional activation by ICSBP contributes to human hematologic malignancies. To investigate the functional cooperation of these 2 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 because of an expansion of a mature myeloid progenitor cell. Furthermore, Nf1 haploinsufficiency and loss of Icsbp contribute synergistically to progression of the myeloproliferative disorder toward 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 2 tumor suppressor genes Nf1 and Icsbp synergize in the induction of leukemias.
authors.affiliation: Leibniz-Institut fuer Molekulare Pharmakologie, Berlin, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Koenigsmann
authors.forename: Cornelia
authors.initials: C
authors.lastname: Rudolph
authors.forename: Sandrine
authors.initials: S
authors.lastname: Sander
authors.forename: Olivia
authors.initials: O
authors.lastname: Kershaw
authors.forename: Achim D
authors.initials: AD
authors.lastname: Gruber
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: Dirk
authors.initials: D
authors.lastname: Carstanjen
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells; D003114:Colony-Forming Units Assay; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells; D050835:Interferon Regulatory Factors / Q000502:physiology*; D007938:Leukemia / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D038042:Myelopoiesis; D009196:Myeloproliferative Disorders / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D025542:Neurofibromin 1 / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099185:Interferon Regulatory Factor-8
chemical_list: D050835:Interferon Regulatory Factors; D025542:Neurofibromin 1; D012333:RNA, Messenger; D000099185:Interferon Regulatory Factor-8