The LMO2 oncogene regulates DNA replication in hematopoietic cells

Oncogenic transcription factors are commonly activated in acute leukemias and subvert normal gene expression networks to reprogram hematopoietic progenitors into preleukemic stem cells, as exemplified by LIM-only 2 (LMO2) in T-cell acute lymphoblastic leukemia (T-ALL). Whether or not these oncoprote...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2016-02, Vol.113 (5), p.1393-1398
Main Authors: Sincennes, Marie-Claude, Humbert, Magali, Grondin, Benoît, Lisi, Véronique, Veiga, Diogo F. T., Haman, André, Cazaux, Christophe, Mashtalir, Nazar, Affar, EL Bachir, Verreault, Alain, Hoang, Trang
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - genetics
Animals
Biological Sciences
Cells
Deoxyribonucleic acid
DNA
DNA Replication - genetics
Enzymes
Gene expression
Genes
Hematopoietic Stem Cells - cytology
Hematopoietic Stem Cells - metabolism
LIM Domain Proteins - genetics
Mice
Replication Origin
S Phase
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Summary:Oncogenic transcription factors are commonly activated in acute leukemias and subvert normal gene expression networks to reprogram hematopoietic progenitors into preleukemic stem cells, as exemplified by LIM-only 2 (LMO2) in T-cell acute lymphoblastic leukemia (T-ALL). Whether or not these oncoproteins interfere with other DNA-dependent processes is largely unexplored. Here, we show that LMO2 is recruited to DNA replication origins by interaction with three essential replication enzymes: DNA polymerase delta (POLD1), DNA primase (PRIM1), and minichromosome 6 (MCM6). Furthermore, tethering LMO2 to synthetic DNA sequences is sufficient to transform these sequences into origins of replication. We next addressed the importance of LMO2 in erythroid and thymocyte development, two lineages in which cell cycle and differentiation are tightly coordinated. Lowering LMO2 levels in erythroid progenitors delays G1-S progression and arrests erythropoietin-dependent cell growth while favoring terminal differentiation. Conversely, ectopic expression in thymocytes induces DNA replication and drives these cells into cell cycle, causing differentiation blockade. Our results define a novel role for LMO2 in directly promoting DNA synthesis and G1-S progression.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1515071113