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.
N1 - Funding Information:
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.
Publisher Copyright:
© 2015 Elsevier Inc.
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 -