Ko, Tun Kiat, Javed, Asif ORCID: 0000-0002-6945-9624, Lee, Kian Leong, Pathiraja, Thushangi N., Liu, Xingliang, Malik, Simeen, Soh, Sheila Xinxuan, Heng, Xiu Ting, Takahashi, Naoto, Tan, Joanna H. J., Bhatia, Ravi, Khng, Alexis J., Chng, Wee-Joo, Sia, Yee Yen, Fruman, David A., Ng, King Pan, Chan, Zhu En, Xie, Kim Jiajing, Hoi, Qiangze, Chan, Cheryl Xueli, Teo, Audrey S. M., Camacho, Oscar Velazquez, Meah, Wee Yang, Khor, Chiea Chuen, Ong, Chin Thing J., Soon, Wei Jia W., Tan, Patrick, Ng, Pauline C., Chuah, Charles, Hillmer, Axel M. and Ong, S. Tiong (2020). An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia. Blood, 135 (26). S. 2337 - 2354. WASHINGTON: AMER SOC HEMATOLOGY. ISSN 1528-0020

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Abstract

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 wholegenome 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 PRCdriven 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 (decitabine1PRC1 inhibitors), novel PRC-silenced tumor suppressor genes (NR4A2), and gene expression signatures predictive of disease progression and drug resistance in CP.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Ko, Tun KiatUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Javed, AsifUNSPECIFIEDorcid.org/0000-0002-6945-9624UNSPECIFIED
Lee, Kian LeongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pathiraja, Thushangi N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liu, XingliangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Malik, SimeenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Soh, Sheila XinxuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heng, Xiu TingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Takahashi, NaotoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tan, Joanna H. J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bhatia, RaviUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khng, Alexis J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chng, Wee-JooUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sia, Yee YenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fruman, David A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ng, King PanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chan, Zhu EnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Xie, Kim JiajingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoi, QiangzeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chan, Cheryl XueliUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Teo, Audrey S. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Camacho, Oscar VelazquezUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meah, Wee YangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khor, Chiea ChuenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ong, Chin Thing J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Soon, Wei Jia W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tan, PatrickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ng, Pauline C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chuah, CharlesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hillmer, Axel M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ong, S. TiongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-329130
DOI: 10.1182/blood.2020004834
Journal or Publication Title: Blood
Volume: 135
Number: 26
Page Range: S. 2337 - 2354
Date: 2020
Publisher: AMER SOC HEMATOLOGY
Place of Publication: WASHINGTON
ISSN: 1528-0020
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENE-EXPRESSION SIGNATURE; NUCLEAR RECEPTOR NURR1; STEM-CELLS; BCR-ABL; TUMOR-SUPPRESSOR; DNA METHYLATION; LYMPHOBLASTIC-LEUKEMIA; MOLECULAR SIGNATURES; REPRESSIVE COMPLEXES; CLONAL EVOLUTIONMultiple languages
HematologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/32913

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