Abstract:
:The erythroleukemia developed by spi-1/PU.1 transgenic mice is a multistage process characterized by an early arrest of the proerythroblast differentiation followed later on by malignant transformation. Herein, we report the presence of acquired mutations in the SCF receptor gene (Kit) in 86% of tumors isolated during the late stage of the disease. Kit mutations affect codon 814 or 818. Ectopic expression of Kit mutants in nonmalignant proerythroblasts confers erythropoietin independence and tumorigenicity to cells. Using PP1, PP2, and imatinib mesylate, we show that Kit mutants are responsible for the autonomous expansion of malignant cells via Erk1/2 and PI3K/Akt activations. These findings represent a proof of principle for oncogenic cooperativity between one proliferative and one differentiation blocking event for the development of an overt leukemia.
journal_name
Cancer Celljournal_title
Cancer cellauthors
Kosmider O,Denis N,Lacout C,Vainchenker W,Dubreuil P,Moreau-Gachelin Fdoi
10.1016/j.ccr.2005.11.009keywords:
subject
Has Abstractpub_date
2005-12-01 00:00:00pages
467-78issue
6eissn
1535-6108issn
1878-3686pii
S1535-6108(05)00365-Xjournal_volume
8pub_type
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