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

Cancer Cell. 2015 Apr 13;27(4):502-15. doi: 10.1016/j.ccell.2015.03.009.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / therapeutic use
  • Cell Differentiation / genetics
  • Cytarabine / therapeutic use
  • DNA Methylation
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Doxorubicin / therapeutic use
  • Epigenesis, Genetic*
  • GATA2 Transcription Factor / genetics
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Haploinsufficiency
  • Leukemia, Myeloid, Acute / genetics*
  • Mutation
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • fms-Like Tyrosine Kinase 3 / genetics*
  • fms-Like Tyrosine Kinase 3 / metabolism

Substances

  • Antineoplastic Agents
  • DNA-Binding Proteins
  • GATA2 Transcription Factor
  • Gata2 protein, mouse
  • Proto-Oncogene Proteins
  • Tet2 protein, mouse
  • Cytarabine
  • Doxorubicin
  • Flt3 protein, mouse
  • fms-Like Tyrosine Kinase 3