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

TitleAn integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia
Authors
KeywordsMyeloid Neoplasia
Plenary Papers
Issue Date2020
PublisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/
Citation
Blood, 2020, v. 135 n. 26, p. 2337-2353 How to Cite?
AbstractTargeted 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.
Persistent Identifierhttp://hdl.handle.net/10722/285432
ISSN
2023 Impact Factor: 21.0
2023 SCImago Journal Rankings: 5.272
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorKiat, TK-
dc.contributor.authorJaved, A-
dc.contributor.authorLeong, KL-
dc.contributor.authorPathiraja, TN-
dc.contributor.authorLIU, X-
dc.contributor.authorMalik, S-
dc.contributor.authorSoh, SX-
dc.contributor.authorHeng, XT-
dc.contributor.authorTakahashi, N-
dc.contributor.authorTan, JHJ-
dc.contributor.authorBhatia, R-
dc.contributor.authorKhng, AJ-
dc.contributor.authorChng, WJ-
dc.contributor.authorSia, YY-
dc.contributor.authorFruman, DA-
dc.contributor.authorNg, KP-
dc.contributor.authorChan, ZE-
dc.contributor.authorXie, KJ-
dc.contributor.authorHoi, Q-
dc.contributor.authorChan, CX-
dc.contributor.authorTeo, ASM-
dc.contributor.authorCamacho, OV-
dc.contributor.authorMeah, WY-
dc.contributor.authorKhor, CC-
dc.contributor.authorOng, CTJ-
dc.contributor.authorSoon, WJW-
dc.contributor.authorTan, P-
dc.contributor.authorNg, PC-
dc.contributor.authorChuah, C-
dc.contributor.authorHillmer, AM-
dc.contributor.authorOng, ST-
dc.date.accessioned2020-08-18T03:53:21Z-
dc.date.available2020-08-18T03:53:21Z-
dc.date.issued2020-
dc.identifier.citationBlood, 2020, v. 135 n. 26, p. 2337-2353-
dc.identifier.issn0006-4971-
dc.identifier.urihttp://hdl.handle.net/10722/285432-
dc.description.abstractTargeted 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.-
dc.languageeng-
dc.publisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/-
dc.relation.ispartofBlood-
dc.rightsThis research was originally published in [Journal Title]. Author(s). Title. [Journal Title]. Year;Vol,Issue:pp-pp. © the American Society of Hematology.-
dc.subjectMyeloid Neoplasia-
dc.subjectPlenary Papers-
dc.titleAn integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia-
dc.typeArticle-
dc.identifier.emailJaved, A: javed@hku.hk-
dc.identifier.authorityJaved, A=rp02386-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1182/blood.2020004834-
dc.identifier.pmid32157296-
dc.identifier.scopuseid_2-s2.0-85087111045-
dc.identifier.hkuros312830-
dc.identifier.volume135-
dc.identifier.issue26-
dc.identifier.spage2337-
dc.identifier.epage2353-
dc.identifier.isiWOS:000547005900008-
dc.publisher.placeUnited States-
dc.identifier.issnl0006-4971-

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