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Chromosome 5q deletion and epigenetic suppression of the gene encoding α-catenin (CTNNA1) in myeloid cell transformation

Abstract

Interstitial loss of all or part of the long arm of chromosome 5, or del(5q), is a frequent clonal chromosomal abnormality in human myelodysplastic syndrome (MDS, a preleukemic disorder) and acute myeloid leukemia (AML)1, and is thought to contribute to the pathogenesis of these diseases by deleting one or more tumor-suppressor genes2. Although a major commonly deleted region (CDR) has been delineated on chromosome band 5q31.1 (refs. 37), attempts to identify tumor suppressors within this band have been unsuccessful. We focused our analysis of gene expression on RNA from primitive leukemia-initiating cells, which harbor 5q deletions8,9, and analyzed 12 genes within the CDR that are expressed by normal hematopoietic stem cells. Here we show that the gene encoding α-catenin (CTNNA1) is expressed at a much lower level in leukemia-initiating stem cells from individuals with AML or MDS with a 5q deletion than in individuals with MDS or AML lacking a 5q deletion or in normal hematopoietic stem cells. Analysis of HL-60 cells, a myeloid leukemia line with deletion of the 5q31 region10,11, showed that the CTNNA1 promoter of the retained allele is suppressed by both methylation and histone deacetylation. Restoration of CTNNA1 expression in HL-60 cells resulted in reduced proliferation and apoptotic cell death. Thus, loss of expression of the α-catenin tumor suppressor in hematopoietic stem cells may provide a growth advantage that contributes to human MDS or AML with del(5q).

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Figure 1: Purification and gene expression analysis of normal HSCs and L-ICs and dual-fluorescence in situ hybridization (D-FISH) analysis of HL-60 cells and purified L-ICs.
Figure 2: Expression levels of CTNNA1 in MDS or AML individuals with or without chromosome 5 abnormalities.
Figure 3: Effects of 5-aza-2'-deoxycytidine (DAC) and trichostatin A (TSA) on CTNNA1 expression and the methylation status of the CTNNA1 CpG island.
Figure 4: Functional consequences of reintroducing CTNNA1 expression into HL-60 cells.

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Acknowledgements

We are grateful to S. Heinrichs and K. Griffith for statistical analysis; D. Adams and the University of Michigan flow cytometry core for assistance in the design and implementation of the sort paradigms used in this study; K. Mrózek for cytogenetic review; L. Moreau and J. Eskenas for assistance with fluorescence in situ hybridization; and J. Gilbert and J. Berman for editorial assistance and critical comments. This work was supported by a Leukemia and Lymphoma Society SCOR grant, the National Natural Science Foundation of China (30525019 to T.X.L.), the Leukemia Clinical Research Foundation and the US National Institutes of Health (grants CA108631 to A.T.L. and J.-P.I.; CA104987 to M.F.C.; and CA101140 to C.D.B.).

Author information

Authors and Affiliations

Authors

Contributions

T.X.L. conducted the RT-PCR, functional experiments and wrote the manuscript. M.W.B. performed the hematopoietic cell sorting and real-time PCR, and wrote the manuscript. J.J. and J.-P.I. did the methylation analysis. W.-S.W. performed the retroviral experiments. M.D. helped with the RT-PCR experiments. M.F.C. and A.T.L. supervised the project. Others contributed to the handling of patient samples and to the editing of the manuscript.

Corresponding author

Correspondence to A Thomas Look.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Expression profile of 28 5q CDR genes in L-ICs derived from del(5q)-V. (PDF 1063 kb)

Supplementary Fig. 2

Immunofluorescence assay of α-catenin protein in sorted normal HSC, and L-ICs. (PDF 1221 kb)

Supplementary Fig. 3

Level of CTNNA1 expression in normal HSCs (CD34+ CD38− Lin−) and leukemia cell lines either untreated or treated with 0.5 μM DAC for 48 hr or 0.3 μM TSA for 24 hr. (PDF 177 kb)

Supplementary Fig. 4

Model for the malignant transformation of α-catenin-deficient HSCs. (PDF 900 kb)

Supplementary Table 1

Clinical characteristics of MDS/AML patients with or without del(5q) (PDF 132 kb)

Supplementary Table 2

Frequency of 5q deletion in HL-60 cells and AML/MDS patients as determined by D-1 FISH. (PDF 95 kb)

Supplementary Table 3

Primer sequences of genes located in 5q31.1 commonly deleted region. (PDF 99 kb)

Supplementary Methods (PDF 59 kb)

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Liu, T., Becker, M., Jelinek, J. et al. Chromosome 5q deletion and epigenetic suppression of the gene encoding α-catenin (CTNNA1) in myeloid cell transformation. Nat Med 13, 78–83 (2007). https://doi.org/10.1038/nm1512

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