期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 5, 页码 1393-1398出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1515071113
关键词
LMO2; cell cycle; DNA replication; hematopoietic cells; T-cell acute lymphoblastic leukemia
资金
- Cancer Research Society, Inc.
- Canadian Institutes for Health Research (CIHR) [MOP111050]
- Canadian Cancer Society Research Institute [019222]
- Leukemia & Lymphoma Society
- CIHR [89928]
- CIHR
- Fonds de Recherche du Quebec-Sante
- Canada Graduate Scholarship Doctoral Award (CIHR)
- Cole Foundation
- Swiss National Foundation [PBBEP3 144798]
- Swiss Foundation for Fellowships in Medicine and Biology
- Novartis [P3SMP3 151720]
- Swiss National Science Foundation (SNF) [P3SMP3_151720, PBBEP3_144798] Funding Source: Swiss National Science Foundation (SNF)
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.
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