Mutational cooperativity linked to combinatorial epigenetic gain of function in acute myeloid leukemia

Alan H. Shih; Yanwen Jiang; Cem Meydan; Kaitlyn Shank; Suveg Pandey; Laura Barreyro; Ileana Antony-Debre; Agnes Viale; Nicholas Socci; Yongming Sun; Alexander Robertson; Magali Cavatore; Elisa deStanchina; Todd Hricik; Franck Rapaport; Brittany Woods; Chen Wei; Megan Hatlen; Muhamed Baljevic; Stephen D. Nimer; Martin Tallman; Elisabeth Paietta; Luisa Cimmino; Iannis Aifantis; Ulrich Steidl; Chris Mason; Ari Melnick; Ross L. Levine

doi:10.1016/j.ccell.2015.03.009

Mutational cooperativity linked to combinatorial epigenetic gain of function in acute myeloid leukemia

Alan H. Shih, Yanwen Jiang, Cem Meydan, Kaitlyn Shank, Suveg Pandey, Laura Barreyro, Ileana Antony-Debre, Agnes Viale, Nicholas Socci, Yongming Sun, Alexander Robertson, Magali Cavatore, Elisa deStanchina, Todd Hricik, Franck Rapaport, Brittany Woods, Chen Wei, Megan Hatlen, Muhamed Baljevic, Stephen D. NimerMartin Tallman, Elisabeth Paietta, Luisa Cimmino, Iannis Aifantis, Ulrich Steidl, Chris Mason, Ari Melnick, Ross L. Levine^*

^*Corresponding author for this work

Medicine, Hematology Oncology Division

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

205 Scopus citations

Abstract

Specific combinations of acute myeloid leukemia (AML) disease alleles, including FLT3 and TET2 mutations, confer distinct biologic features and adverse outcome. We generated mice with mutations in Tet2 and Flt3, which resulted in fully penetrant, lethal AML. Multipotent Tet2^-/-;Flt3^ITD progenitors (LSK CD48⁺CD150^-) propagate disease in secondary recipients and were refractory to standard AML chemotherapy and FLT3-targeted therapy. Flt3^ITD mutations and Tet2 loss cooperatively remodeled DNA methylation and gene expression to an extent not seen with either mutant allele alone, including at the Gata2 locus. Re-expression of Gata2 induced differentiation in AML stem cells and attenuated leukemogenesis. TET2 and FLT3 mutations cooperatively induce AML, with a defined leukemia stem cell population characterized by site-specific changes in DNA methylation and gene expression.

Original language	English (US)
Pages (from-to)	502-515
Number of pages	14
Journal	Cancer cell
Volume	27
Issue number	4
DOIs	https://doi.org/10.1016/j.ccell.2015.03.009
State	Published - Apr 13 2015

Funding

This work was supported by a Gabrielle’s Angel Fund grant to R.L.L. and A.M., a Leukemia Lymphoma Society (LLS) Translational Research grant to R.L.L. and I.A., grant CA172636-01 to R.L.L., I.A., and A.M., and the Samuel Waxman Cancer Research Center. C.M. is supported by R01HG006798 and R01NS076465; S.D.N. and M.H. by R01CA166835; and MSKCC cores by P30 CA008748. A.M. is a Burroughs Wellcome Clinical Translational Scholar and supported by the Sackler Center for Biomedical and Physical Sciences. R.L.L. is an LLS Scholar. A.H.S. is supported by the Conquer Cancer Foundation and LLS. Y.J. is an ASH Scholar. We would like to thank Scott Lowe for reagents and advice on chemotherapy studies. Y.S. and A.R. are employees of Life Technologies.

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

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

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Shih, A. H., Jiang, Y., Meydan, C., Shank, K., Pandey, S., Barreyro, L., Antony-Debre, I., Viale, A., Socci, N., Sun, Y., Robertson, A., Cavatore, M., deStanchina, E., Hricik, T., Rapaport, F., Woods, B., Wei, C., Hatlen, M., Baljevic, M., ... Levine, R. L. (2015). Mutational cooperativity linked to combinatorial epigenetic gain of function in acute myeloid leukemia. Cancer cell, 27(4), 502-515. https://doi.org/10.1016/j.ccell.2015.03.009

@article{f2b989895fab43779b2c07c03365505c,

title = "Mutational cooperativity linked to combinatorial epigenetic gain of function in acute myeloid leukemia",

abstract = "Specific combinations of acute myeloid leukemia (AML) disease alleles, including FLT3 and TET2 mutations, confer distinct biologic features and adverse outcome. We generated mice with mutations in Tet2 and Flt3, which resulted in fully penetrant, lethal AML. Multipotent Tet2-/-;Flt3ITD progenitors (LSK CD48+CD150-) propagate disease in secondary recipients and were refractory to standard AML chemotherapy and FLT3-targeted therapy. Flt3ITD mutations and Tet2 loss cooperatively remodeled DNA methylation and gene expression to an extent not seen with either mutant allele alone, including at the Gata2 locus. Re-expression of Gata2 induced differentiation in AML stem cells and attenuated leukemogenesis. TET2 and FLT3 mutations cooperatively induce AML, with a defined leukemia stem cell population characterized by site-specific changes in DNA methylation and gene expression.",

author = "Shih, \{Alan H.\} and Yanwen Jiang and Cem Meydan and Kaitlyn Shank and Suveg Pandey and Laura Barreyro and Ileana Antony-Debre and Agnes Viale and Nicholas Socci and Yongming Sun and Alexander Robertson and Magali Cavatore and Elisa deStanchina and Todd Hricik and Franck Rapaport and Brittany Woods and Chen Wei and Megan Hatlen and Muhamed Baljevic and Nimer, \{Stephen D.\} and Martin Tallman and Elisabeth Paietta and Luisa Cimmino and Iannis Aifantis and Ulrich Steidl and Chris Mason and Ari Melnick and Levine, \{Ross L.\}",

note = "Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = apr,

day = "13",

doi = "10.1016/j.ccell.2015.03.009",

language = "English (US)",

volume = "27",

pages = "502--515",

journal = "Cancer cell",

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Shih, AH, Jiang, Y, Meydan, C, Shank, K, Pandey, S, Barreyro, L, Antony-Debre, I, Viale, A, Socci, N, Sun, Y, Robertson, A, Cavatore, M, deStanchina, E, Hricik, T, Rapaport, F, Woods, B, Wei, C, Hatlen, M, Baljevic, M, Nimer, SD, Tallman, M, Paietta, E, Cimmino, L, Aifantis, I, Steidl, U, Mason, C, Melnick, A & Levine, RL 2015, 'Mutational cooperativity linked to combinatorial epigenetic gain of function in acute myeloid leukemia', Cancer cell, vol. 27, no. 4, pp. 502-515. https://doi.org/10.1016/j.ccell.2015.03.009

TY - JOUR

T1 - Mutational cooperativity linked to combinatorial epigenetic gain of function in acute myeloid leukemia

AU - Shih, Alan H.

AU - Jiang, Yanwen

AU - Meydan, Cem

AU - Shank, Kaitlyn

AU - Pandey, Suveg

AU - Barreyro, Laura

AU - Antony-Debre, Ileana

AU - Viale, Agnes

AU - Socci, Nicholas

AU - Sun, Yongming

AU - Robertson, Alexander

AU - Cavatore, Magali

AU - deStanchina, Elisa

AU - Hricik, Todd

AU - Rapaport, Franck

AU - Woods, Brittany

AU - Wei, Chen

AU - Hatlen, Megan

AU - Baljevic, Muhamed

AU - Nimer, Stephen D.

AU - Tallman, Martin

AU - Paietta, Elisabeth

AU - Cimmino, Luisa

AU - Aifantis, Iannis

AU - Steidl, Ulrich

AU - Mason, Chris

AU - Melnick, Ari

AU - Levine, Ross L.

PY - 2015/4/13

Y1 - 2015/4/13

N2 - Specific combinations of acute myeloid leukemia (AML) disease alleles, including FLT3 and TET2 mutations, confer distinct biologic features and adverse outcome. We generated mice with mutations in Tet2 and Flt3, which resulted in fully penetrant, lethal AML. Multipotent Tet2-/-;Flt3ITD progenitors (LSK CD48+CD150-) propagate disease in secondary recipients and were refractory to standard AML chemotherapy and FLT3-targeted therapy. Flt3ITD mutations and Tet2 loss cooperatively remodeled DNA methylation and gene expression to an extent not seen with either mutant allele alone, including at the Gata2 locus. Re-expression of Gata2 induced differentiation in AML stem cells and attenuated leukemogenesis. TET2 and FLT3 mutations cooperatively induce AML, with a defined leukemia stem cell population characterized by site-specific changes in DNA methylation and gene expression.

AB - Specific combinations of acute myeloid leukemia (AML) disease alleles, including FLT3 and TET2 mutations, confer distinct biologic features and adverse outcome. We generated mice with mutations in Tet2 and Flt3, which resulted in fully penetrant, lethal AML. Multipotent Tet2-/-;Flt3ITD progenitors (LSK CD48+CD150-) propagate disease in secondary recipients and were refractory to standard AML chemotherapy and FLT3-targeted therapy. Flt3ITD mutations and Tet2 loss cooperatively remodeled DNA methylation and gene expression to an extent not seen with either mutant allele alone, including at the Gata2 locus. Re-expression of Gata2 induced differentiation in AML stem cells and attenuated leukemogenesis. TET2 and FLT3 mutations cooperatively induce AML, with a defined leukemia stem cell population characterized by site-specific changes in DNA methylation and gene expression.

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U2 - 10.1016/j.ccell.2015.03.009

DO - 10.1016/j.ccell.2015.03.009

M3 - Article

C2 - 25873173

AN - SCOPUS:84928011690

SN - 1535-6108

VL - 27

SP - 502

EP - 515

JO - Cancer cell

JF - Cancer cell

IS - 4

ER -

Mutational cooperativity linked to combinatorial epigenetic gain of function in acute myeloid leukemia

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

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