Abstract：
:The multistage process of cancer formation is driven by the progressive acquisition of somatic mutations. Replication stress creates genomic instability in mammals. Using a well-defined multistep leukemia model driven by Spi-1/PU.1 overexpression in the mouse and Spi-1/PU.1-overexpressing human leukemic cells, we investigated the relationship between DNA replication and cancer progression. Here, using DNA molecular combing and flow cytometry methods, we show that Spi-1 increases the speed of replication by acting specifically on elongation rather than enhancing origin firing. This shortens the S-phase duration. Combining data from Spi-1 knockdown in murine cells with Spi-1 overexpression in human cells, we provide evidence that inappropriate Spi-1 expression is directly responsible for the replication alteration observed. Importantly, the acceleration of replication progression coincides with an increase in the frequency of genomic mutations without inducing DNA breakage. Thus, we propose that the hitherto unsuspected role for spi-1 oncogene in promoting replication elongation and genomic mutation promotes blastic progression during leukemic development.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Rimmelé P,Komatsu J,Hupé P,Roulin C,Barillot E,Dutreix M,Conseiller E,Bensimon A,Moreau-Gachelin F,Guillouf Cdoi
10.1158/0008-5472.CAN-09-4691subject
Has Abstractpub_date
2010-09-01 00:00:00pages
6757-66issue
17eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-09-4691journal_volume
70pub_type
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