An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia

  • Tun Kiat Ko
    Cancer & Stem Cell Biology Signature Research Programme, Duke-NUS Medical School, Singapore;
  • Asif Javed
    Cancer Therapeutics & Stratified Oncology, Genome Institute of Singapore, Singapore;
  • Kian Leong Lee
    Cancer & Stem Cell Biology Signature Research Programme, Duke-NUS Medical School, Singapore;
  • Thushangi N. Pathiraja
    Cancer Therapeutics & Stratified Oncology, Genome Institute of Singapore, Singapore;
  • Xingliang Liu
    Cancer Therapeutics & Stratified Oncology, Genome Institute of Singapore, Singapore;
  • Simeen Malik
    Cancer & Stem Cell Biology Signature Research Programme, Duke-NUS Medical School, Singapore;
  • Sheila Xinxuan Soh
    Cancer & Stem Cell Biology Signature Research Programme, Duke-NUS Medical School, Singapore;
  • Xiu Ting Heng
    Cancer Therapeutics & Stratified Oncology, Genome Institute of Singapore, Singapore;
  • Naoto Takahashi
    Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan;
  • Joanna H. J. Tan
    Cancer Therapeutics & Stratified Oncology, Genome Institute of Singapore, Singapore;
  • Ravi Bhatia
    Division of Hematology-Oncology, Department of Medicine, University of Alabama Birmingham, Birmingham, AL;
  • Alexis J. Khng
    Cancer Therapeutics & Stratified Oncology, Genome Institute of Singapore, Singapore;
  • Wee-Joo Chng
    Department of Hematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore;
  • Yee Yen Sia
    Cancer Therapeutics & Stratified Oncology, Genome Institute of Singapore, Singapore;
  • David A. Fruman
    Department of Molecular Biology & Biochemistry, University of California, Irvine, CA;
  • King Pan Ng
    Cancer & Stem Cell Biology Signature Research Programme, Duke-NUS Medical School, Singapore;
  • Zhu En Chan
    Cancer & Stem Cell Biology Signature Research Programme, Duke-NUS Medical School, Singapore;
  • Kim Jiajing Xie
    Cancer & Stem Cell Biology Signature Research Programme, Duke-NUS Medical School, Singapore;
  • Qiangze Hoi
    Computational and Systems Biology, Genome Institute of Singapore, Singapore;
  • Cheryl Xueli Chan
    Cancer Therapeutics & Stratified Oncology, Genome Institute of Singapore, Singapore;
  • Audrey S. M. Teo
    Cancer Therapeutics & Stratified Oncology, Genome Institute of Singapore, Singapore;
  • Oscar Velazquez Camacho
    Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany;
  • Wee Yang Meah
    Human Genetics, Genome Institute of Singapore, Singapore;
  • Chiea Chuen Khor
    Human Genetics, Genome Institute of Singapore, Singapore;
  • Chin Thing J. Ong
    Next Generation Sequencing Platform, Genome Institute of Singapore, Singapore;
  • Wei Jia W. Soon
    Next Generation Sequencing Platform, Genome Institute of Singapore, Singapore;
  • Patrick Tan
    Cancer & Stem Cell Biology Signature Research Programme, Duke-NUS Medical School, Singapore;
  • Pauline C. Ng
    Computational and Systems Biology, Genome Institute of Singapore, Singapore;
  • Charles Chuah
    Department of Haematology, Singapore General Hospital, Singapore;
  • Axel M. Hillmer
    Cancer Therapeutics & Stratified Oncology, Genome Institute of Singapore, Singapore;
  • S. Tiong Ong
    Cancer & Stem Cell Biology Signature Research Programme, Duke-NUS Medical School, Singapore;

説明

<jats:title>Abstract</jats:title> <jats:p>Targeted therapies against the BCR-ABL1 kinase have revolutionized treatment of chronic phase (CP) chronic myeloid leukemia (CML). In contrast, management of blast crisis (BC) CML remains challenging because BC cells acquire complex molecular alterations that confer stemness features to progenitor populations and resistance to BCR-ABL1 tyrosine kinase inhibitors. Comprehensive models of BC transformation have proved elusive because of the rarity and genetic heterogeneity of BC, but are important for developing biomarkers predicting BC progression and effective therapies. To better understand BC, we performed an integrated multiomics analysis of 74 CP and BC samples using whole-genome and exome sequencing, transcriptome and methylome profiling, and chromatin immunoprecipitation followed by high-throughput sequencing. Employing pathway-based analysis, we found the BC genome was significantly enriched for mutations affecting components of the polycomb repressive complex (PRC) pathway. While transcriptomically, BC progenitors were enriched and depleted for PRC1- and PRC2-related gene sets respectively. By integrating our data sets, we determined that BC progenitors undergo PRC-driven epigenetic reprogramming toward a convergent transcriptomic state. Specifically, PRC2 directs BC DNA hypermethylation, which in turn silences key genes involved in myeloid differentiation and tumor suppressor function via so-called epigenetic switching, whereas PRC1 represses an overlapping and distinct set of genes, including novel BC tumor suppressors. On the basis of these observations, we developed an integrated model of BC that facilitated the identification of combinatorial therapies capable of reversing BC reprogramming (decitabine+PRC1 inhibitors), novel PRC-silenced tumor suppressor genes (NR4A2), and gene expression signatures predictive of disease progression and drug resistance in CP.</jats:p>

収録刊行物

  • Blood

    Blood 135 (26), 2337-2353, 2020-06-25

    American Society of Hematology

被引用文献 (3)*注記

もっと見る

詳細情報 詳細情報について

問題の指摘

ページトップへ