Kit-activating mutations cooperate with Spi-1/PU.1 overexpression to promote tumorigenic progression during erythroleukemia in mice.
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.
Kosmider
Olivier
O
Inserm U528, Institut Curie, 26 rue d'Ulm, 75248 Paris cedex 05, France.
Denis
Nicole
N
Lacout
Catherine
C
Vainchenker
William
W
Dubreuil
Patrice
P
Moreau-Gachelin
Françoise
F
D000818:Animals; D001549:Benzamides; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D013997:Time Factors; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics; D000099232:Proto-Oncogene Protein Spi-1
D001549:Benzamides; D000068877:Imatinib Mesylate; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D019009:Proto-Oncogene Proteins c-kit; D011720:Pyrazoles; D011743:Pyrimidines; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; C412373:AG 1879