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Dissection of the Function and Pre-clinical Targeting of IGF1R in Acute Lymphoblastic Leukemia Induced by the BCR-ABL Fusion Oncoprotein

Filippo Della MarinaUniversité Paris Diderot - Paris 7 (1970-2019).

出版	2015
URL	http://books.google.com.hk/books?id=HHlKzQEACAAJ&hl=&source=gbs_api

註釋In recent years several inhibitors have been developed targeting the tyrosine kinase activity of the BCR-ABL fusion oncoprotein in Chronic Myeloid Leukemia (CML). Unlike the favorable clinical response observed in CML cases, BCR¬ABL` B-cell Acute Lymphoblastic Leukemias (B-ALLs) remain of poor prognosis. The likely reason for this aggressive behavior is the presence in these leukemias of additional genetic alterations. The most frequent of these is the mono-or bi-allelic deletion of the gene encoding the Ikaros transcription factor (IKZF1), observed in over 83% of patients. Our laboratory has studied the functional consequences of IKZF1 haploinsufficiency in a BCR-ABL-induced B-ALL mouse model and identified an Ikaros-dependent transcriptomic signature in these leukemic cells. This signature includes the overexpression of IGF1R, a tyrosine kinase receptor for IGF1. Based on these premises my PhD thesis work shows (i) that pharmacological inhibition of IGF1R sensitizes Ikaros-deficient BCR-ABL+ B-ALL to the antiproliferative and pro-apoptotic effects of Nilotinib, (ii) that IGF1R gene deletion impairs in vivo expansion of these leukemias in vivo, (iii) that treatment of leukemic mice with NVP-AEW541 (an IGF1R inhibitor) in combination with Nilotinib significantly increases survival of treated mice as compared to control mice, (iv) that the increased survival of treated mice is accompanied by an increase in apoptosis and a decrease in the proliferation of leukemic cells and (v) that inhibition of the AKT/mTORC1/S6K signalling pathway is a point of convergence of these inhibitor combination.