Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation

Andrew A. Lane; Bjoern Chapuy; Charles Y. Lin; Trevor Tivey; Hubo Li; Elizabeth C. Townsend; Diederik Van Bodegom; Tovah A. Day; Shuo Chieh Wu; Huiyun Liu; Akinori Yoda; Gabriela Alexe; Anna C. Schinzel; Timothy J. Sullivan; Sébastien Malinge; Jordan E. Taylor; Kimberly Stegmaier; Jacob D. Jaffe; Michael Bustin; Geertruy Te Kronnie; Shai Izraeli; Marian H. Harris; Kristen E. Stevenson; Donna Neuberg; Lewis B. Silverman; Stephen E. Sallan; James E. Bradner; William C. Hahn; John D. Crispino; David Pellman; David M. Weinstock

doi:10.1038/ng.2949

Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation

Andrew A. Lane^*, Bjoern Chapuy, Charles Y. Lin, Trevor Tivey, Hubo Li, Elizabeth C. Townsend, Diederik Van Bodegom, Tovah A. Day, Shuo Chieh Wu, Huiyun Liu, Akinori Yoda, Gabriela Alexe, Anna C. Schinzel, Timothy J. Sullivan, Sébastien Malinge, Jordan E. Taylor, Kimberly Stegmaier, Jacob D. Jaffe, Michael Bustin, Geertruy Te KronnieShai Izraeli, Marian H. Harris, Kristen E. Stevenson, Donna Neuberg, Lewis B. Silverman, Stephen E. Sallan, James E. Bradner, William C. Hahn, John D. Crispino, David Pellman, David M. Weinstock

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

113 Scopus citations

Abstract

Down syndrome confers a 20-fold increased risk of B cell acute lymphoblastic leukemia (B-ALL), and polysomy 21 is the most frequent somatic aneuploidy among all B-ALLs. Yet the mechanistic links between chromosome 21 triplication and B-ALL remain undefined. Here we show that germline triplication of only 31 genes orthologous to human chromosome 21q22 confers mouse progenitor B cell self renewal in vitro, maturation defects in vivo and B-ALL with either the BCR-ABL fusion protein or CRLF2 with activated JAK2. Chromosome 21q22 triplication suppresses histone H3 Lys27 trimethylation (H3K27me3) in progenitor B cells and B-ALLs, and 'bivalent' genes with both H3K27me3 and H3K4me3 at their promoters in wild-type progenitor B cells are preferentially overexpressed in triplicated cells. Human B-ALLs with polysomy 21 are distinguished by their overexpression of genes marked with H3K27me3 in multiple cell types. Overexpression of HMGN1, a nucleosome remodeling protein encoded on chromosome 21q22 (refs. 3,4,5), suppresses H3K27me3 and promotes both B cell proliferation in vitro and B-ALL in vivo.

Original language	English (US)
Pages (from-to)	618-623
Number of pages	6
Journal	Nature Genetics
Volume	46
Issue number	6
DOIs	https://doi.org/10.1038/ng.2949
State	Published - Jun 2014

Funding

We thank N. Kopp and A. Schlauch for technical assistance, M. Busslinger (Research Institute of Molecular Pathology, Vienna) for the Pax5+/− mice and M. Oshimura (Tottori University) for A9 cells carrying human chromosome 21. This research was supported by the Conquer Cancer Foundation (A.A.L.), the Lauri Strauss Leukemia Foundation (A.A.L.), the Leukemia and Lymphoma Society (A.A.L.), the Alex Lemonade Stand Foundation (A.A.L., H. Li and D.P.), the US Department of Defense (C.Y.L.), the Israel Science Foundation (S.I.), the US Israel Binational Foundation (J.D.C. and S.I.), the Stellato Fund (D.M.W.), US National Institutes of Health/National Cancer Institute R01 awards CA15198-01 and CA172387-A01 (D.M.W.) and a Translational Research Award from the Leukemia and Lymphoma Society (J.D.C. and D.M.W.).

ASJC Scopus subject areas

Genetics

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Lane, A. A., Chapuy, B., Lin, C. Y., Tivey, T., Li, H., Townsend, E. C., Van Bodegom, D., Day, T. A., Wu, S. C., Liu, H., Yoda, A., Alexe, G., Schinzel, A. C., Sullivan, T. J., Malinge, S., Taylor, J. E., Stegmaier, K., Jaffe, J. D., Bustin, M., ... Weinstock, D. M. (2014). Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation. Nature Genetics, 46(6), 618-623. https://doi.org/10.1038/ng.2949

@article{1018fff0795946d28343a4cdac0b4b03,

title = "Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation",

abstract = "Down syndrome confers a 20-fold increased risk of B cell acute lymphoblastic leukemia (B-ALL), and polysomy 21 is the most frequent somatic aneuploidy among all B-ALLs. Yet the mechanistic links between chromosome 21 triplication and B-ALL remain undefined. Here we show that germline triplication of only 31 genes orthologous to human chromosome 21q22 confers mouse progenitor B cell self renewal in vitro, maturation defects in vivo and B-ALL with either the BCR-ABL fusion protein or CRLF2 with activated JAK2. Chromosome 21q22 triplication suppresses histone H3 Lys27 trimethylation (H3K27me3) in progenitor B cells and B-ALLs, and 'bivalent' genes with both H3K27me3 and H3K4me3 at their promoters in wild-type progenitor B cells are preferentially overexpressed in triplicated cells. Human B-ALLs with polysomy 21 are distinguished by their overexpression of genes marked with H3K27me3 in multiple cell types. Overexpression of HMGN1, a nucleosome remodeling protein encoded on chromosome 21q22 (refs. 3,4,5), suppresses H3K27me3 and promotes both B cell proliferation in vitro and B-ALL in vivo.",

author = "Lane, {Andrew A.} and Bjoern Chapuy and Lin, {Charles Y.} and Trevor Tivey and Hubo Li and Townsend, {Elizabeth C.} and {Van Bodegom}, Diederik and Day, {Tovah A.} and Wu, {Shuo Chieh} and Huiyun Liu and Akinori Yoda and Gabriela Alexe and Schinzel, {Anna C.} and Sullivan, {Timothy J.} and S{\'e}bastien Malinge and Taylor, {Jordan E.} and Kimberly Stegmaier and Jaffe, {Jacob D.} and Michael Bustin and {Te Kronnie}, Geertruy and Shai Izraeli and Harris, {Marian H.} and Stevenson, {Kristen E.} and Donna Neuberg and Silverman, {Lewis B.} and Sallan, {Stephen E.} and Bradner, {James E.} and Hahn, {William C.} and Crispino, {John D.} and David Pellman and Weinstock, {David M.}",

note = "Funding Information: We thank N. Kopp and A. Schlauch for technical assistance, M. Busslinger (Research Institute of Molecular Pathology, Vienna) for the Pax5+/− mice and M. Oshimura (Tottori University) for A9 cells carrying human chromosome 21. This research was supported by the Conquer Cancer Foundation (A.A.L.), the Lauri Strauss Leukemia Foundation (A.A.L.), the Leukemia and Lymphoma Society (A.A.L.), the Alex Lemonade Stand Foundation (A.A.L., H. Li and D.P.), the US Department of Defense (C.Y.L.), the Israel Science Foundation (S.I.), the US Israel Binational Foundation (J.D.C. and S.I.), the Stellato Fund (D.M.W.), Funding Information: US National Institutes of Health/National Cancer Institute R01 awards CA15198-01 and CA172387-A01 (D.M.W.) and a Translational Research Award from the Leukemia and Lymphoma Society (J.D.C. and D.M.W.).",

year = "2014",

month = jun,

doi = "10.1038/ng.2949",

language = "English (US)",

volume = "46",

pages = "618--623",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "6",

}

Lane, AA, Chapuy, B, Lin, CY, Tivey, T, Li, H, Townsend, EC, Van Bodegom, D, Day, TA, Wu, SC, Liu, H, Yoda, A, Alexe, G, Schinzel, AC, Sullivan, TJ, Malinge, S, Taylor, JE, Stegmaier, K, Jaffe, JD, Bustin, M, Te Kronnie, G, Izraeli, S, Harris, MH, Stevenson, KE, Neuberg, D, Silverman, LB, Sallan, SE, Bradner, JE, Hahn, WC, Crispino, JD, Pellman, D & Weinstock, DM 2014, 'Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation', Nature Genetics, vol. 46, no. 6, pp. 618-623. https://doi.org/10.1038/ng.2949

TY - JOUR

T1 - Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation

AU - Lane, Andrew A.

AU - Chapuy, Bjoern

AU - Lin, Charles Y.

AU - Tivey, Trevor

AU - Li, Hubo

AU - Townsend, Elizabeth C.

AU - Van Bodegom, Diederik

AU - Day, Tovah A.

AU - Wu, Shuo Chieh

AU - Liu, Huiyun

AU - Yoda, Akinori

AU - Alexe, Gabriela

AU - Schinzel, Anna C.

AU - Sullivan, Timothy J.

AU - Malinge, Sébastien

AU - Taylor, Jordan E.

AU - Stegmaier, Kimberly

AU - Jaffe, Jacob D.

AU - Bustin, Michael

AU - Te Kronnie, Geertruy

AU - Izraeli, Shai

AU - Harris, Marian H.

AU - Stevenson, Kristen E.

AU - Neuberg, Donna

AU - Silverman, Lewis B.

AU - Sallan, Stephen E.

AU - Bradner, James E.

AU - Hahn, William C.

AU - Crispino, John D.

AU - Pellman, David

AU - Weinstock, David M.

N1 - Funding Information: We thank N. Kopp and A. Schlauch for technical assistance, M. Busslinger (Research Institute of Molecular Pathology, Vienna) for the Pax5+/− mice and M. Oshimura (Tottori University) for A9 cells carrying human chromosome 21. This research was supported by the Conquer Cancer Foundation (A.A.L.), the Lauri Strauss Leukemia Foundation (A.A.L.), the Leukemia and Lymphoma Society (A.A.L.), the Alex Lemonade Stand Foundation (A.A.L., H. Li and D.P.), the US Department of Defense (C.Y.L.), the Israel Science Foundation (S.I.), the US Israel Binational Foundation (J.D.C. and S.I.), the Stellato Fund (D.M.W.), Funding Information: US National Institutes of Health/National Cancer Institute R01 awards CA15198-01 and CA172387-A01 (D.M.W.) and a Translational Research Award from the Leukemia and Lymphoma Society (J.D.C. and D.M.W.).

PY - 2014/6

Y1 - 2014/6

N2 - Down syndrome confers a 20-fold increased risk of B cell acute lymphoblastic leukemia (B-ALL), and polysomy 21 is the most frequent somatic aneuploidy among all B-ALLs. Yet the mechanistic links between chromosome 21 triplication and B-ALL remain undefined. Here we show that germline triplication of only 31 genes orthologous to human chromosome 21q22 confers mouse progenitor B cell self renewal in vitro, maturation defects in vivo and B-ALL with either the BCR-ABL fusion protein or CRLF2 with activated JAK2. Chromosome 21q22 triplication suppresses histone H3 Lys27 trimethylation (H3K27me3) in progenitor B cells and B-ALLs, and 'bivalent' genes with both H3K27me3 and H3K4me3 at their promoters in wild-type progenitor B cells are preferentially overexpressed in triplicated cells. Human B-ALLs with polysomy 21 are distinguished by their overexpression of genes marked with H3K27me3 in multiple cell types. Overexpression of HMGN1, a nucleosome remodeling protein encoded on chromosome 21q22 (refs. 3,4,5), suppresses H3K27me3 and promotes both B cell proliferation in vitro and B-ALL in vivo.

AB - Down syndrome confers a 20-fold increased risk of B cell acute lymphoblastic leukemia (B-ALL), and polysomy 21 is the most frequent somatic aneuploidy among all B-ALLs. Yet the mechanistic links between chromosome 21 triplication and B-ALL remain undefined. Here we show that germline triplication of only 31 genes orthologous to human chromosome 21q22 confers mouse progenitor B cell self renewal in vitro, maturation defects in vivo and B-ALL with either the BCR-ABL fusion protein or CRLF2 with activated JAK2. Chromosome 21q22 triplication suppresses histone H3 Lys27 trimethylation (H3K27me3) in progenitor B cells and B-ALLs, and 'bivalent' genes with both H3K27me3 and H3K4me3 at their promoters in wild-type progenitor B cells are preferentially overexpressed in triplicated cells. Human B-ALLs with polysomy 21 are distinguished by their overexpression of genes marked with H3K27me3 in multiple cell types. Overexpression of HMGN1, a nucleosome remodeling protein encoded on chromosome 21q22 (refs. 3,4,5), suppresses H3K27me3 and promotes both B cell proliferation in vitro and B-ALL in vivo.

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Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation

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