ASXL1 Mutations Promote Myeloid Transformation through Loss of PRC2-Mediated Gene Repression

Omar Abdel-Wahab; Mazhar Adli; Lindsay M. LaFave; Jie Gao; Todd Hricik; Alan H. Shih; Suveg Pandey; Jay P. Patel; Young Rock Chung; Richard Koche; Fabiana Perna; Xinyang Zhao; Jordan E. Taylor; Christopher Y. Park; Martin Carroll; Ari Melnick; Stephen D. Nimer; Jacob D. Jaffe; Iannis Aifantis; Bradley E. Bernstein; Ross L. Levine

doi:10.1016/j.ccr.2012.06.032

ASXL1 Mutations Promote Myeloid Transformation through Loss of PRC2-Mediated Gene Repression

Omar Abdel-Wahab, Mazhar Adli, Lindsay M. LaFave, Jie Gao, Todd Hricik, Alan H. Shih, Suveg Pandey, Jay P. Patel, Young Rock Chung, Richard Koche, Fabiana Perna, Xinyang Zhao, Jordan E. Taylor, Christopher Y. Park, Martin Carroll, Ari Melnick, Stephen D. Nimer, Jacob D. Jaffe, Iannis Aifantis, Bradley E. Bernstein^*Ross L. Levine

^*Corresponding author for this work

Obstetrics and Gynecology

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

488 Scopus citations

Abstract

Recurrent somaticASXL1 mutations occur in patients with myelodysplastic syndrome, myeloproliferative neoplasms, and acute myeloid leukemia, and are associated with adverse outcome. Despite the genetic and clinical data implicating ASXL1 mutations in myeloid malignancies, the mechanisms of transformation by ASXL1 mutations are not understood. Here, we identify that ASXL1 mutations result in loss of polycomb repressive complex 2 (PRC2)-mediated histone H3 lysine 27 (H3K27) tri-methylation. Through integration of microarray data with genome-wide histone modification ChIP-Seq data, we identify targets of ASXL1 repression, including the posterior HOXA cluster that is known to contribute to myeloid transformation. We demonstrate that ASXL1 associates with the PRC2, and that loss of ASXL1 in vivo collaborates with NRASG12D to promote myeloid leukemogenesis.

Original language	English (US)
Pages (from-to)	180-193
Number of pages	14
Journal	Cancer cell
Volume	22
Issue number	2
DOIs	https://doi.org/10.1016/j.ccr.2012.06.032
State	Published - Aug 14 2012

Funding

This work was supported by a grant from the Starr Cancer Consortium to R.L.L. and B.E.B., by grants from the Gabrielle's Angel Fund to R.L.L. and O.A.-W., by a grant from the Anna Fuller Fund to R.L.L., and by an NHLBI grant to B.E.B. (5U01HL100395). I.A. and B.E.B. are Howard Hughes Medical Institute Early Career Scientists. A.M. is a Burroughs Wellcome Clinical Translational Scholar and Scholar of the Leukemia and Lymphoma Society. X.Z. and S.D.N. are supported by a Leukemia and Lymphoma Society SCOR award, and F.P. is supported by an American Italian Cancer Foundation award. O.A.-W. is an American Society of Hematology Basic Research Fellow and is supported by a grant from the NIH K08 Clinical Investigator Award (1K08CA160647-01). J.P.P. is supported by an American Society of Hematology Trainee Research Award.

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccr.2012.06.032

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Abdel-Wahab, O., Adli, M., LaFave, L. M., Gao, J., Hricik, T., Shih, A. H., Pandey, S., Patel, J. P., Chung, Y. R., Koche, R., Perna, F., Zhao, X., Taylor, J. E., Park, C. Y., Carroll, M., Melnick, A., Nimer, S. D., Jaffe, J. D., Aifantis, I., ... Levine, R. L. (2012). ASXL1 Mutations Promote Myeloid Transformation through Loss of PRC2-Mediated Gene Repression. Cancer cell, 22(2), 180-193. https://doi.org/10.1016/j.ccr.2012.06.032

@article{6909d7b0abb843d8be818abb4c9c97ee,

title = "ASXL1 Mutations Promote Myeloid Transformation through Loss of PRC2-Mediated Gene Repression",

abstract = "Recurrent somaticASXL1 mutations occur in patients with myelodysplastic syndrome, myeloproliferative neoplasms, and acute myeloid leukemia, and are associated with adverse outcome. Despite the genetic and clinical data implicating ASXL1 mutations in myeloid malignancies, the mechanisms of transformation by ASXL1 mutations are not understood. Here, we identify that ASXL1 mutations result in loss of polycomb repressive complex 2 (PRC2)-mediated histone H3 lysine 27 (H3K27) tri-methylation. Through integration of microarray data with genome-wide histone modification ChIP-Seq data, we identify targets of ASXL1 repression, including the posterior HOXA cluster that is known to contribute to myeloid transformation. We demonstrate that ASXL1 associates with the PRC2, and that loss of ASXL1 in vivo collaborates with NRASG12D to promote myeloid leukemogenesis.",

author = "Omar Abdel-Wahab and Mazhar Adli and LaFave, {Lindsay M.} and Jie Gao and Todd Hricik and Shih, {Alan H.} and Suveg Pandey and Patel, {Jay P.} and Chung, {Young Rock} and Richard Koche and Fabiana Perna and Xinyang Zhao and Taylor, {Jordan E.} and Park, {Christopher Y.} and Martin Carroll and Ari Melnick and Nimer, {Stephen D.} and Jaffe, {Jacob D.} and Iannis Aifantis and Bernstein, {Bradley E.} and Levine, {Ross L.}",

note = "Funding Information: This work was supported by a grant from the Starr Cancer Consortium to R.L.L. and B.E.B., by grants from the Gabrielle's Angel Fund to R.L.L. and O.A.-W., by a grant from the Anna Fuller Fund to R.L.L., and by an NHLBI grant to B.E.B. (5U01HL100395). I.A. and B.E.B. are Howard Hughes Medical Institute Early Career Scientists. A.M. is a Burroughs Wellcome Clinical Translational Scholar and Scholar of the Leukemia and Lymphoma Society. X.Z. and S.D.N. are supported by a Leukemia and Lymphoma Society SCOR award, and F.P. is supported by an American Italian Cancer Foundation award. O.A.-W. is an American Society of Hematology Basic Research Fellow and is supported by a grant from the NIH K08 Clinical Investigator Award (1K08CA160647-01). J.P.P. is supported by an American Society of Hematology Trainee Research Award. ",

year = "2012",

month = aug,

day = "14",

doi = "10.1016/j.ccr.2012.06.032",

language = "English (US)",

volume = "22",

pages = "180--193",

journal = "Cancer cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "2",

}

Abdel-Wahab, O, Adli, M, LaFave, LM, Gao, J, Hricik, T, Shih, AH, Pandey, S, Patel, JP, Chung, YR, Koche, R, Perna, F, Zhao, X, Taylor, JE, Park, CY, Carroll, M, Melnick, A, Nimer, SD, Jaffe, JD, Aifantis, I, Bernstein, BE & Levine, RL 2012, 'ASXL1 Mutations Promote Myeloid Transformation through Loss of PRC2-Mediated Gene Repression', Cancer cell, vol. 22, no. 2, pp. 180-193. https://doi.org/10.1016/j.ccr.2012.06.032

TY - JOUR

T1 - ASXL1 Mutations Promote Myeloid Transformation through Loss of PRC2-Mediated Gene Repression

AU - Abdel-Wahab, Omar

AU - Adli, Mazhar

AU - LaFave, Lindsay M.

AU - Gao, Jie

AU - Hricik, Todd

AU - Shih, Alan H.

AU - Pandey, Suveg

AU - Patel, Jay P.

AU - Chung, Young Rock

AU - Koche, Richard

AU - Perna, Fabiana

AU - Zhao, Xinyang

AU - Taylor, Jordan E.

AU - Park, Christopher Y.

AU - Carroll, Martin

AU - Melnick, Ari

AU - Nimer, Stephen D.

AU - Jaffe, Jacob D.

AU - Aifantis, Iannis

AU - Bernstein, Bradley E.

AU - Levine, Ross L.

N1 - Funding Information: This work was supported by a grant from the Starr Cancer Consortium to R.L.L. and B.E.B., by grants from the Gabrielle's Angel Fund to R.L.L. and O.A.-W., by a grant from the Anna Fuller Fund to R.L.L., and by an NHLBI grant to B.E.B. (5U01HL100395). I.A. and B.E.B. are Howard Hughes Medical Institute Early Career Scientists. A.M. is a Burroughs Wellcome Clinical Translational Scholar and Scholar of the Leukemia and Lymphoma Society. X.Z. and S.D.N. are supported by a Leukemia and Lymphoma Society SCOR award, and F.P. is supported by an American Italian Cancer Foundation award. O.A.-W. is an American Society of Hematology Basic Research Fellow and is supported by a grant from the NIH K08 Clinical Investigator Award (1K08CA160647-01). J.P.P. is supported by an American Society of Hematology Trainee Research Award.

PY - 2012/8/14

Y1 - 2012/8/14

N2 - Recurrent somaticASXL1 mutations occur in patients with myelodysplastic syndrome, myeloproliferative neoplasms, and acute myeloid leukemia, and are associated with adverse outcome. Despite the genetic and clinical data implicating ASXL1 mutations in myeloid malignancies, the mechanisms of transformation by ASXL1 mutations are not understood. Here, we identify that ASXL1 mutations result in loss of polycomb repressive complex 2 (PRC2)-mediated histone H3 lysine 27 (H3K27) tri-methylation. Through integration of microarray data with genome-wide histone modification ChIP-Seq data, we identify targets of ASXL1 repression, including the posterior HOXA cluster that is known to contribute to myeloid transformation. We demonstrate that ASXL1 associates with the PRC2, and that loss of ASXL1 in vivo collaborates with NRASG12D to promote myeloid leukemogenesis.

AB - Recurrent somaticASXL1 mutations occur in patients with myelodysplastic syndrome, myeloproliferative neoplasms, and acute myeloid leukemia, and are associated with adverse outcome. Despite the genetic and clinical data implicating ASXL1 mutations in myeloid malignancies, the mechanisms of transformation by ASXL1 mutations are not understood. Here, we identify that ASXL1 mutations result in loss of polycomb repressive complex 2 (PRC2)-mediated histone H3 lysine 27 (H3K27) tri-methylation. Through integration of microarray data with genome-wide histone modification ChIP-Seq data, we identify targets of ASXL1 repression, including the posterior HOXA cluster that is known to contribute to myeloid transformation. We demonstrate that ASXL1 associates with the PRC2, and that loss of ASXL1 in vivo collaborates with NRASG12D to promote myeloid leukemogenesis.

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UR - http://www.scopus.com/inward/citedby.url?scp=84865152223&partnerID=8YFLogxK

U2 - 10.1016/j.ccr.2012.06.032

DO - 10.1016/j.ccr.2012.06.032

M3 - Article

C2 - 22897849

AN - SCOPUS:84865152223

SN - 1535-6108

VL - 22

SP - 180

EP - 193

JO - Cancer cell

JF - Cancer cell

IS - 2

ER -

ASXL1 Mutations Promote Myeloid Transformation through Loss of PRC2-Mediated Gene Repression

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UN SDGs

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