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

Blood
Tun Kiat KoS Tiong Ong

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 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 tra...Continue Reading

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Citations

Jun 26, 2020·Blood·George Giotopoulos, Brian J P Huntly
Sep 11, 2020·Leukemia·Helong Zhao, Michael W Deininger
Nov 20, 2020·Journal of Clinical Medicine·Rüdiger Hehlmann
Jan 14, 2021·Cells·Valentina R MinciacchiDaniela S Krause
Mar 29, 2021·Blood Reviews·Afaf E G Osman, Michael W Deininger
May 5, 2021·Leukemia & Lymphoma·Shady Adnan-AwadSatu Mustjoki

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