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Leukemic survival factor SALL4 contributes to defective DNA damage repair
- Source :
- Oncogene
- Publication Year :
- 2015
-
Abstract
- SALL4 is aberrantly expressed in human myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We have generated a SALL4 transgenic (SALL4B Tg) mouse model with pre-leukemic MDS-like symptoms that transform to AML over time. This makes our mouse model applicable for studying human MDS/AML diseases. Characterization of the leukemic initiation population in this model leads to the discovery that Fancl (Fanconi anemia, complementation group L) is down-regulated in SALL4B Tg leukemic and pre-leukemic cells. Similar to the reported Fanconi anemia (FA) mouse model, chromosomal instability with radial changes that can be detected in pre-leukemic SALL4B Tg bone marrow (BM) cells after DNA damage challenge. Results from additional studies using DNA damage repair reporter assays support a role of SALL4 in inhibiting the homologous recombination pathway. Intriguingly, unlike the FA mouse model, after DNA damage challenge, SALL4B Tg BM cells can survive and generate hematopoietic colonies. We further elucidated that the mechanism by which SALL4 promotes cell survival is through Bcl2 activation. Overall, our studies demonstrate for the first time that SALL4 has a negative impact in DNA damage repair, and support the model of dual functional properties of SALL4 in leukemogenesis through inhibiting DNA damage repair and promoting cell survival.
- Subjects :
- 0301 basic medicine
Male
Cancer Research
DNA End-Joining Repair
DNA Repair
Fancl
Gene Expression
Mice
Fanconi anemia
hemic and lymphatic diseases
Cluster Analysis
FANCL
Homologous Recombination
Bone Marrow Transplantation
SALL4
Fanconi Anemia Complementation Group D2 Protein
Cell cycle
3. Good health
DNA-Binding Proteins
Leukemia, Myeloid, Acute
Female
Bcl2
DNA repair
DNA damage
Mitomycin
Karyotype
Fanconi Anemia Complementation Group L Protein
Bone Marrow Cells
Mice, Transgenic
Biology
Article
03 medical and health sciences
Chromosomal Instability
Genetics
medicine
Animals
Humans
Molecular Biology
Myelodysplastic syndromes
Gene Expression Profiling
medicine.disease
Hematopoietic Stem Cells
Molecular biology
eye diseases
Genes, bcl-2
Disease Models, Animal
030104 developmental biology
Gene Expression Regulation
Myelodysplastic Syndromes
Homologous recombination
DNA Damage
Transcription Factors
Subjects
Details
- ISSN :
- 14765594
- Volume :
- 35
- Issue :
- 47
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....7920a17e1206c6ffee543e5d3613ca3b