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MYBL2 is a sub-haploinsufficient tumor suppressor gene in myeloid malignancy
- Source :
- eLife, vol 2, iss 2, eLife, eLife, Vol 2 (2013)
- Publication Year :
- 2013
- Publisher :
- eScholarship, University of California, 2013.
-
Abstract
- A common deleted region (CDR) in both myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) affects the long arm of chromosome 20 and has been predicted to harbor a tumor suppressor gene. Here we show that MYBL2, a gene within the 20q CDR, is expressed at sharply reduced levels in CD34+ cells from most MDS cases (65%; n = 26), whether or not they harbor 20q abnormalities. In a murine competitive reconstitution model, Mybl2 knockdown by RNAi to 20–30% of normal levels in multipotent hematopoietic progenitors resulted in clonal dominance of these ‘sub-haploinsufficient’ cells, which was reflected in all blood cell lineages. By 6 months post-transplantation, the reconstituted mice had developed a clonal myeloproliferative/myelodysplastic disorder originating from the cells with aberrantly reduced Mybl2 expression. We conclude that downregulation of MYBL2 activity below levels predicted by classical haploinsufficiency underlies the clonal expansion of hematopoietic progenitors in a large fraction of human myeloid malignancies. DOI: http://dx.doi.org/10.7554/eLife.00825.001<br />eLife digest Blood cells are produced within bone marrow by specialized stem cells and progenitor cells. Abnormalities in this process lead to a group of diseases known as myeloid malignancies, which include acute myeloid leukaemia—in which the bone marrow produces abnormal white blood cells—and myelodysplastic syndromes, which are caused by too few mature blood cells being produced. Many individuals affected by these disorders possess a shortened form of chromosome 20 that lacks a number of genes. This deletion is only ever seen in one of their two copies of the chromosome—suggesting that at least some of these genes are essential for survival—but the identity of the gene(s) that are associated with the increased risk of myeloid malignancies is unknown. Now, Heinrichs et al. have uncovered a key tumor suppressor among those genes frequently lost on chromosome 20. The gene, which is called MYBL2, encodes a transcription factor that helps to control the cell division cycle. Myeloid malignancy patients lacking one copy of this gene showed levels of MYBL2 expression that were less than 50% of those in healthy individuals. This suggests that additional mechanisms must be acting to reduce expression of their remaining copy of the gene. Surprisingly, MYBL2 levels were also reduced in myeloid malignancy patients who possessed two intact copies of chromosome 20, indicating that loss of a single copy represents only one mechanism to reduce MYBL2 expression, i.e., the ‘tip-of-the-iceberg’. Hence, this finding reveals a more general role for MYBL2 as it indicates that more patients are likely to be affected by altered expression of this gene. To confirm their findings from studies in patients, Heinrichs et al. used gene silencing techniques to reduce the expression of MYBL2 in mice and showed that this induced symptoms of myeloid malignancies in the animals. Moreover, injection of modified cells from these animals into healthy mice also induced symptoms in the recipients. The modified cells are able to expand more robustly than normal cells, and this dominance induced by downregulation of the tumor suppressor increases the risk of malignancy. In addition to revealing a new tumor suppressor gene and its contribution to myeloid malignancies, the study by Heinrichs et al. highlights the importance of gene dosage in mediating the effects of tumor suppressors. DOI: http://dx.doi.org/10.7554/eLife.00825.002
- Subjects :
- Myeloid
Mouse
Medizin
CD34
MYBL2
Cell Cycle Proteins
Haploinsufficiency
PHENOTYPE
0302 clinical medicine
Stem Cell Research - Nonembryonic - Human
2.1 Biological and endogenous factors
Genes, Tumor Suppressor
TRANSCRIPTION
Biology (General)
Aetiology
Cancer
0303 health sciences
Gene knockdown
General Neuroscience
Hematology
General Medicine
CANCER
3. Good health
Haematopoiesis
Blood
medicine.anatomical_structure
Genes and Chromosomes
030220 oncology & carcinogenesis
Dosage Compensation
Medicine
Tumor Suppressor
Research Article
Biotechnology
Human
EXPRESSION
20q CDR
Tumor suppressor gene
QH301-705.5
Science
education
B-MYB
Biology
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
Rare Diseases
ARRAY ANALYSIS
Genetic
Dosage Compensation, Genetic
Genetics
medicine
Humans
HEMATOPOIETIC STEM-CELLS
Human Biology and Medicine
030304 developmental biology
Myeloproliferative Disorders
IDENTIFICATION
General Immunology and Microbiology
Myelodysplastic syndromes
5Q-SYNDROME
Stem Cell Research
medicine.disease
REDUCTION
Genes
Myelodysplastic Syndromes
Karyotyping
Immunology
Cancer research
Trans-Activators
3111 Biomedicine
Biochemistry and Cell Biology
Chromosome 20
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- eLife, vol 2, iss 2, eLife, eLife, Vol 2 (2013)
- Accession number :
- edsair.doi.dedup.....ffbf4acd141e17d31c4c4b1297222a12