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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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KNN classification for normal karyotype patient samples.A k-nearest-neighbor (KNN) classification model for patient samples was trained on our gene expression data set of CD34+ cells with or without MYBL2 knockdown by RNAi. Upper panel: KNN classification for the presence (negative values) or absence (positive values) for the MYBL2 signature using Euclidean distance (k = 3) to predict the class label by a majority vote. Lower panel: gene expression profile of MYBL2 signature genes.DOI:http://dx.doi.org/10.7554/eLife.00825.011
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fig3s1: KNN classification for normal karyotype patient samples.A k-nearest-neighbor (KNN) classification model for patient samples was trained on our gene expression data set of CD34+ cells with or without MYBL2 knockdown by RNAi. Upper panel: KNN classification for the presence (negative values) or absence (positive values) for the MYBL2 signature using Euclidean distance (k = 3) to predict the class label by a majority vote. Lower panel: gene expression profile of MYBL2 signature genes.DOI:http://dx.doi.org/10.7554/eLife.00825.011

Mentions: To determine which MDS patients with a normal karyotype have an ‘MYBL2-low’ expression signature, we first analyzed the expression levels of MYBL2-regulated genes in the CD34+ cells from our 18 normal-karyotype MDS cases, using a k-nearest neighbor (KNN) classifier and Euclidean distance (k = 3) to predict the class label by a majority vote. 10 of these cases (56%) were classified as MYBL2 low, while the remaining eight cases had an MYBL2 signature that was statistically similar to that of normal CD34+ controls (Figure 3—figure supplement 1). To validate our classification algorithm using a separate dataset, we then interrogated the normal karyotype cases (n = 94) reported by Pellagati et al. (Pellagatti et al., 2010), identifying a MYBL2-low signature in 36 cases (38%), most of which (30 cases) were identified at a confidence level of 1.0. 58 cases (62%) had a normal MYBL2 signature (Figure 3). Thus, we were able to confirm in an independent cohort that the ‘MYBL2 low’ signature is present in CD34+ cells from a substantial fraction of normal-karyotype MDS cases.10.7554/eLife.00825.010Figure 3.KNN classification for normal karyotype patient samples of an independent data set (Pellagatti et al., 2010).


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)

KNN classification for normal karyotype patient samples.A k-nearest-neighbor (KNN) classification model for patient samples was trained on our gene expression data set of CD34+ cells with or without MYBL2 knockdown by RNAi. Upper panel: KNN classification for the presence (negative values) or absence (positive values) for the MYBL2 signature using Euclidean distance (k = 3) to predict the class label by a majority vote. Lower panel: gene expression profile of MYBL2 signature genes.DOI:http://dx.doi.org/10.7554/eLife.00825.011
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3s1: KNN classification for normal karyotype patient samples.A k-nearest-neighbor (KNN) classification model for patient samples was trained on our gene expression data set of CD34+ cells with or without MYBL2 knockdown by RNAi. Upper panel: KNN classification for the presence (negative values) or absence (positive values) for the MYBL2 signature using Euclidean distance (k = 3) to predict the class label by a majority vote. Lower panel: gene expression profile of MYBL2 signature genes.DOI:http://dx.doi.org/10.7554/eLife.00825.011
Mentions: To determine which MDS patients with a normal karyotype have an ‘MYBL2-low’ expression signature, we first analyzed the expression levels of MYBL2-regulated genes in the CD34+ cells from our 18 normal-karyotype MDS cases, using a k-nearest neighbor (KNN) classifier and Euclidean distance (k = 3) to predict the class label by a majority vote. 10 of these cases (56%) were classified as MYBL2 low, while the remaining eight cases had an MYBL2 signature that was statistically similar to that of normal CD34+ controls (Figure 3—figure supplement 1). To validate our classification algorithm using a separate dataset, we then interrogated the normal karyotype cases (n = 94) reported by Pellagati et al. (Pellagatti et al., 2010), identifying a MYBL2-low signature in 36 cases (38%), most of which (30 cases) were identified at a confidence level of 1.0. 58 cases (62%) had a normal MYBL2 signature (Figure 3). Thus, we were able to confirm in an independent cohort that the ‘MYBL2 low’ signature is present in CD34+ cells from a substantial fraction of normal-karyotype MDS cases.10.7554/eLife.00825.010Figure 3.KNN classification for normal karyotype patient samples of an independent data set (Pellagatti et al., 2010).

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