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

Publication ,  Journal Article
Ko, TK; Javed, A; Lee, KL; Pathiraja, TN; Liu, X; Malik, S; Soh, SX; Heng, XT; Takahashi, N; Tan, JHJ; Bhatia, R; Khng, AJ; Chng, W-J ...
Published in: Blood
June 25, 2020

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.

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Published In

Blood

DOI

EISSN

1528-0020

Publication Date

June 25, 2020

Volume

135

Issue

26

Start / End Page

2337 / 2353

Location

United States

Related Subject Headings

  • Whole Genome Sequencing
  • Transcriptome
  • Polycomb Repressive Complex 2
  • Polycomb Repressive Complex 1
  • Mutation
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Immunology
  • Humans
  • High-Throughput Nucleotide Sequencing
  • Gene Ontology
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Ko, T. K., Javed, A., Lee, K. L., Pathiraja, T. N., Liu, X., Malik, S., … Ong, S. T. (2020). An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia. Blood, 135(26), 2337–2353. https://doi.org/10.1182/blood.2020004834
Ko, Tun Kiat, Asif Javed, Kian Leong Lee, Thushangi N. Pathiraja, Xingliang Liu, Simeen Malik, Sheila Xinxuan Soh, et al. “An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia.Blood 135, no. 26 (June 25, 2020): 2337–53. https://doi.org/10.1182/blood.2020004834.
Ko TK, Javed A, Lee KL, Pathiraja TN, Liu X, Malik S, et al. An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia. Blood. 2020 Jun 25;135(26):2337–53.
Ko, Tun Kiat, et al. “An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia.Blood, vol. 135, no. 26, June 2020, pp. 2337–53. Pubmed, doi:10.1182/blood.2020004834.
Ko TK, Javed A, Lee KL, Pathiraja TN, Liu X, Malik S, Soh SX, Heng XT, Takahashi N, Tan JHJ, Bhatia R, Khng AJ, Chng W-J, Sia YY, Fruman DA, Ng KP, Chan ZE, Xie KJ, Hoi Q, Chan CX, Teo ASM, Velazquez Camacho O, Meah WY, Khor CC, Ong CTJ, Soon WJW, Tan P, Ng PC, Chuah C, Hillmer AM, Ong ST. An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia. Blood. 2020 Jun 25;135(26):2337–2353.

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

June 25, 2020

Volume

135

Issue

26

Start / End Page

2337 / 2353

Location

United States

Related Subject Headings

  • Whole Genome Sequencing
  • Transcriptome
  • Polycomb Repressive Complex 2
  • Polycomb Repressive Complex 1
  • Mutation
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Immunology
  • Humans
  • High-Throughput Nucleotide Sequencing
  • Gene Ontology