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Cancers 2012, 4(4), 1050-1066; doi:10.3390/cancers4041050

Mouse Lymphoblastic Leukemias Induced by Aberrant Prdm14 Expression Demonstrate Widespread Copy Number Alterations Also Found in Human ALL

1
Baylor College of Medicine, Department of Pediatrics, Texas Children’s Cancer and Hematology Centers, One Baylor Plaza, Houston, TX 77030, USA
2
Baylor College of Medicine, Dan L. Duncan Cancer Center, One Baylor Plaza, Houston, TX 77030, USA
3
Baylor College of Medicine, Department of Molecular and Human Genetics, One Baylor Plaza, Houston, TX 77030, USA
4
Baylor College of Medicine, Interdepartmental Program in Translational Biology and Molecular Medicine, One Baylor Plaza, Houston, TX 77030, USA
*
Author to whom correspondence should be addressed.
Received: 26 July 2012 / Revised: 2 October 2012 / Accepted: 9 October 2012 / Published: 18 October 2012
(This article belongs to the Special Issue Leukemia)
View Full-Text   |   Download PDF [968 KB, 19 October 2012; original version 18 October 2012]   |  

Abstract

Aberrant expression and activation of oncogenes in somatic cells has been associated with cancer initiation. Required for reacquisition of pluripotency in the developing germ cell, PRDM14 initiates lymphoblastic leukemia when misexpressed in murine bone marrow. Activation of pluripotency in somatic cells can lead to aneuploidy and copy number alterations during iPS cell generation, and we hypothesized that PRDM14-induced lymphoblastic leukemias would demonstrate significant chromosomal damage. High-resolution oligo array comparative genomic hybridization demonstrated infrequent aneuploidy but frequent amplification and deletion, with amplifications occurring in a 5:1 ratio with deletions. Many deletions (i.e., Cdkn2a, Ebf1, Pax5, Ikzf1) involved B-cell development genes and tumor suppressor genes, recapitulating deletions occurring in human leukemia. Pathways opposing senescence were frequently deactivated via Cdkn2a deletion or Tbx2 amplification, with corollary gene expression. Additionally, gene expression studies of abnormal pre-leukemic B-precursors showed downregulation of genes involved in chromosomal stability (i.e., Xrcc6) and failure to upregulate DNA repair pathways. We propose a model of leukemogenesis, triggered by pluripotency genes like Prdm14, which involves ongoing DNA damage and failure to activate non-homologous end-joining secondary to aberrant gene expression. View Full-Text
Keywords: PRDM14; lymphoblastic leukemia; pluripotency; CGH; leukemia; DNA damage; DNA repair; CDKN2A; TBX2 PRDM14; lymphoblastic leukemia; pluripotency; CGH; leukemia; DNA damage; DNA repair; CDKN2A; TBX2
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Simko, S.J.; Voicu, H.; Carofino, B.L.; Justice, M.J. Mouse Lymphoblastic Leukemias Induced by Aberrant Prdm14 Expression Demonstrate Widespread Copy Number Alterations Also Found in Human ALL. Cancers 2012, 4, 1050-1066.

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