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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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Related in: MedlinePlus

Flow cytometric analysis of the LSK population in the bone marrow of mice upon reconstitution with Mybl2 shRNA-expressing cells.The analysis was performed in control animals (left panel) and in animals with Mybl2 downregulation (middle and right panel). Vertical bars designate median values. Populations were labeled according to the following markers: CD150+/CD48- (HSC), CD150-/CD48- (MPP) and CD150-/CD48+ (LRP).DOI:http://dx.doi.org/10.7554/eLife.00825.023
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fig7s2: Flow cytometric analysis of the LSK population in the bone marrow of mice upon reconstitution with Mybl2 shRNA-expressing cells.The analysis was performed in control animals (left panel) and in animals with Mybl2 downregulation (middle and right panel). Vertical bars designate median values. Populations were labeled according to the following markers: CD150+/CD48- (HSC), CD150-/CD48- (MPP) and CD150-/CD48+ (LRP).DOI:http://dx.doi.org/10.7554/eLife.00825.023

Mentions: To identify the cells principally involved in the clonal dominance associated with this disorder, we analyzed the Lin−/Sca1+/Kit+ (LSK) bone marrow cells of the affected mice (n = 12) in comparison to controls. Within the LSK population of GFP+ or RFP+ Mybl2-knockdown bone marrow cells, HSCs (CD150+/CD48−) were diminished, MPPs (CD150−/CD48−) were maintained and LRPs (CD150−/CD48+) were increased compared to unlabeled, non-transduced cells. Thus, the clonal dominance due to low Mybl2 levels is first evident as an increased percentage of cells in the LRP fraction. (Figure 7—figure supplement 2).


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)

Flow cytometric analysis of the LSK population in the bone marrow of mice upon reconstitution with Mybl2 shRNA-expressing cells.The analysis was performed in control animals (left panel) and in animals with Mybl2 downregulation (middle and right panel). Vertical bars designate median values. Populations were labeled according to the following markers: CD150+/CD48- (HSC), CD150-/CD48- (MPP) and CD150-/CD48+ (LRP).DOI:http://dx.doi.org/10.7554/eLife.00825.023
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig7s2: Flow cytometric analysis of the LSK population in the bone marrow of mice upon reconstitution with Mybl2 shRNA-expressing cells.The analysis was performed in control animals (left panel) and in animals with Mybl2 downregulation (middle and right panel). Vertical bars designate median values. Populations were labeled according to the following markers: CD150+/CD48- (HSC), CD150-/CD48- (MPP) and CD150-/CD48+ (LRP).DOI:http://dx.doi.org/10.7554/eLife.00825.023
Mentions: To identify the cells principally involved in the clonal dominance associated with this disorder, we analyzed the Lin−/Sca1+/Kit+ (LSK) bone marrow cells of the affected mice (n = 12) in comparison to controls. Within the LSK population of GFP+ or RFP+ Mybl2-knockdown bone marrow cells, HSCs (CD150+/CD48−) were diminished, MPPs (CD150−/CD48−) were maintained and LRPs (CD150−/CD48+) were increased compared to unlabeled, non-transduced cells. Thus, the clonal dominance due to low Mybl2 levels is first evident as an increased percentage of cells in the LRP fraction. (Figure 7—figure supplement 2).

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