Emerging molecular subtypes and therapeutic targets in B-cell precursor acute lymphoblastic leukemia

Abstract

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by genetic alterations with high heterogeneity. Precise subtypes with distinct genomic and/or gene expression patterns have been recently revealed using high-throughput sequencing technology. Most of these profiles are associated with recurrent non-overlapping rearrangements or hotspot point mutations that are analogous to the established subtypes, such as DUX4 rearrangements, MEF2D rearrangements, ZNF384/ZNF362 rearrangements, NUTM1 rearrangements, BCL2/MYC and/or BCL6 rearrangements, ETV6-RUNX1-like gene expression, PAX5alt (diverse PAX5 alterations, including rearrangements, intragenic amplifications, or mutations), and hotspot mutations PAX5 (p.Pro80Arg) with biallelic PAX5 alterations, IKZF1 (p.Asn159Tyr), and ZEB2 (p.His1038Arg). These molecular subtypes could be classified by gene expression patterns with RNA-seq technology. Refined molecular classification greatly improved the treatment strategy. Multiagent therapy regimens, including target inhibitors (e.g., imatinib), immunomodulators, monoclonal antibodies, and chimeric antigen receptor T-cell (CAR-T) therapy, are transforming the clinical practice from chemotherapy drugs to personalized medicine in the field of risk-directed disease management. We provide an update on our knowledge of emerging molecular subtypes and therapeutic targets in BCP-ALL.

Keywords

BCP-ALL / subtypes / translocation / aneuploidy / sequence mutations

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 82070147, 81570122, and 81770205), the National Key Research and Development Program (No. 2016YFC0902800), the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (No. 20161303), the Innovation Foundation for Doctoral Students of Shanghai Jiao Tong University School of Medicine (Research Grant BXJ201815), and the Center for HPC at Shanghai Jiao Tong University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Compliance with ethical guidelines

Jianfeng Li, Yuting Dai, Liang Wu, Ming Zhang, Wen Ouyang, Jinyan Huang, and Saijuan Chen declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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