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Nf1 haploinsufficiency and Icsbp deficiency synergize in the development of leukemias

Leibniz-Institut fuer Molekulare Pharmakologie, Berlin, Germany.
Blood (Impact Factor: 10.43). 03/2009; 113(19):4690-701. DOI: 10.1182/blood-2008-05-158485
Source: PubMed

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.

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    • "cooperating with other oncogenic events as has been dem - onstrated in a mouse model of Nf1 haploinsuffiency and deficiency of the interferon consensus sequence binding protein ( Koenigsmann et al . , 2009 ) . Noonan - syndrome is an autosomal dominant developmental disorder showing germ - line mutations in the PTPN11 , SOS1 , KRAS or RAF1 gene ( Tartaglia et al . , 2001 ; Pandit et al . , 2007 ; Razzaque et al . , 2007 ; Roberts et al . , 2007 ) . t - AML has been reported in this syndrome along with myeloproliferative neoplasms and juve"
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