Transcriptional memory of cells of origin overrides β-catenin requirement of MLL cancer stem cells

EMBO J. 2017 Nov 2;36(21):3139-3155. doi: 10.15252/embj.201797994. Epub 2017 Oct 4.

Abstract

While β-catenin has been demonstrated as an essential molecule and therapeutic target for various cancer stem cells (CSCs) including those driven by MLL fusions, here we show that transcriptional memory from cells of origin predicts AML patient survival and allows β-catenin-independent transformation in MLL-CSCs derived from hematopoietic stem cell (HSC)-enriched LSK population but not myeloid-granulocyte progenitors. Mechanistically, β-catenin regulates expression of downstream targets of a key transcriptional memory gene, Hoxa9 that is highly enriched in LSK-derived MLL-CSCs and helps sustain leukemic self-renewal. Suppression of Hoxa9 sensitizes LSK-derived MLL-CSCs to β-catenin inhibition resulting in abolishment of CSC transcriptional program and transformation ability. In addition, further molecular and functional analyses identified Prmt1 as a key common downstream mediator for β-catenin/Hoxa9 functions in LSK-derived MLL-CSCs. Together, these findings not only uncover an unexpectedly important role of cells of origin transcriptional memory in regulating CSC self-renewal, but also reveal a novel molecular network mediated by β-catenin/Hoxa9/Prmt1 in governing leukemic self-renewal.

Keywords: Hoxa9; MLL leukemia; Prmt1; Wnt/β‐catenin; cells of origin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Ly / genetics
  • Antigens, Ly / metabolism
  • Cell Proliferation
  • Cell Survival
  • Disease Models, Animal
  • Gene Expression Profiling
  • Gene Expression Regulation, Leukemic*
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / pathology
  • Homeodomain Proteins / antagonists & inhibitors
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / mortality
  • Leukemia, Myeloid, Acute / pathology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Protein-Arginine N-Methyltransferases / genetics
  • Protein-Arginine N-Methyltransferases / metabolism
  • Proto-Oncogene Proteins c-kit / genetics
  • Proto-Oncogene Proteins c-kit / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Signal Transduction
  • Survival Analysis
  • Transcription, Genetic*
  • beta Catenin / genetics*
  • beta Catenin / metabolism

Substances

  • Antigens, Ly
  • CTNNB1 protein, human
  • Homeodomain Proteins
  • Ly6a protein, mouse
  • Membrane Proteins
  • RNA, Small Interfering
  • Repressor Proteins
  • beta Catenin
  • homeobox protein HOXA9
  • PRMT1 protein, human
  • Protein-Arginine N-Methyltransferases
  • Proto-Oncogene Proteins c-kit