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MYBL2 is a sub-haploinsufficient tumor suppressor gene in myeloid malignancy.

Heinrichs S, Conover LF, Bueso-Ramos CE, Kilpivaara O, Stevenson K, Neuberg D, Loh ML, Wu WS, Rodig SJ, Garcia-Manero G, Kantarjian HM, Look AT - Elife (2013)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Transfusion Medicine , University Hospital Essen , Essen , Germany ; Department of Pediatric Oncology , Dana-Farber Cancer Institute , Boston , United States.

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.

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Analysis of Mybl2 expression in context with mir-29a and mir-30e expression in selected patient samples and controls.(A) Confirmation of microarray-based MYBL2 gene expression data (white bars) by qRT-PCR analysis (black bars). Here, the same cDNA reaction was used for mRNA and miRNA expression analysis. (B) Relative expression levels of mir-30e and mir-29a determined by qRT-PCR analysis. Normalization was performed to three control genes.DOI:http://dx.doi.org/10.7554/eLife.00825.013
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fig4s1: Analysis of Mybl2 expression in context with mir-29a and mir-30e expression in selected patient samples and controls.(A) Confirmation of microarray-based MYBL2 gene expression data (white bars) by qRT-PCR analysis (black bars). Here, the same cDNA reaction was used for mRNA and miRNA expression analysis. (B) Relative expression levels of mir-30e and mir-29a determined by qRT-PCR analysis. Normalization was performed to three control genes.DOI:http://dx.doi.org/10.7554/eLife.00825.013

Mentions: We also considered that the upregulation of one or more miRNAs targeting MYBL2 might explain our results. We pursued this notion in a subset of patient samples (seven with low MYBL2 expression and two with normal MYBL2 expression, together with three controls) by analyzing the expression levels of mir-29a and mir-30e. Both of these miRNAs target MYBL2 (Han et al., 2010; Martinez et al., 2011), with aberrant expression of mir-29a leading to clonal dominance and acute myeloid leukemia (Han et al., 2010). Our results show upregulation of either mir-29a or mir-30e in three cases with MYBL2 downregulation, but not in controls or cases with normal MYBL2 expression (Figure 4—figure supplement 1). Thus, overexpression of miRNAs targeting MYBL2 affords an attractive mechanism by which MYBL2 expression levels are lowered in a substantial fraction of MDS cases.


MYBL2 is a sub-haploinsufficient tumor suppressor gene in myeloid malignancy.

Heinrichs S, Conover LF, Bueso-Ramos CE, Kilpivaara O, Stevenson K, Neuberg D, Loh ML, Wu WS, Rodig SJ, Garcia-Manero G, Kantarjian HM, Look AT - Elife (2013)

Analysis of Mybl2 expression in context with mir-29a and mir-30e expression in selected patient samples and controls.(A) Confirmation of microarray-based MYBL2 gene expression data (white bars) by qRT-PCR analysis (black bars). Here, the same cDNA reaction was used for mRNA and miRNA expression analysis. (B) Relative expression levels of mir-30e and mir-29a determined by qRT-PCR analysis. Normalization was performed to three control genes.DOI:http://dx.doi.org/10.7554/eLife.00825.013
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3713455&req=5

fig4s1: Analysis of Mybl2 expression in context with mir-29a and mir-30e expression in selected patient samples and controls.(A) Confirmation of microarray-based MYBL2 gene expression data (white bars) by qRT-PCR analysis (black bars). Here, the same cDNA reaction was used for mRNA and miRNA expression analysis. (B) Relative expression levels of mir-30e and mir-29a determined by qRT-PCR analysis. Normalization was performed to three control genes.DOI:http://dx.doi.org/10.7554/eLife.00825.013
Mentions: We also considered that the upregulation of one or more miRNAs targeting MYBL2 might explain our results. We pursued this notion in a subset of patient samples (seven with low MYBL2 expression and two with normal MYBL2 expression, together with three controls) by analyzing the expression levels of mir-29a and mir-30e. Both of these miRNAs target MYBL2 (Han et al., 2010; Martinez et al., 2011), with aberrant expression of mir-29a leading to clonal dominance and acute myeloid leukemia (Han et al., 2010). Our results show upregulation of either mir-29a or mir-30e in three cases with MYBL2 downregulation, but not in controls or cases with normal MYBL2 expression (Figure 4—figure supplement 1). Thus, overexpression of miRNAs targeting MYBL2 affords an attractive mechanism by which MYBL2 expression levels are lowered in a substantial fraction of MDS cases.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Transfusion Medicine , University Hospital Essen , Essen , Germany ; Department of Pediatric Oncology , Dana-Farber Cancer Institute , Boston , United States.

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.

Show MeSH
Related in: MedlinePlus