Replication timing alterations in leukemia affect clinically relevant chromosome domains

Juan Carlos Rivera-Mulia, Takayo Sasaki, Claudia Trevilla-Garcia, Naoto Nakamichi, David J.H.F. Knapp, Colin A. Hammond, Bill H. Chang, Jeffrey W. Tyner, Meenakshi Devidas, Jared Zimmerman, Kyle N. Klein, Vivek Somasundaram, Brian J. Druker, Tanja A. Gruber, Amnon Koren, Connie J. Eaves, David M. Gilbert

Research output: Contribution to journalArticle

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Abstract

Human B-cell precursor acute lymphoid leukemias (BCP-ALLs) comprise a group of genetically and clinically distinct disease entities with features of differentiation arrest at known stages of normal B-lineage differentiation. We previously showed that BCP-ALL cells display unique and clonally heritable, stable DNA replication timing (RT) programs (ie, programs describing the variable order of replication and subnuclear 3D architecture of megabase-scale chromosomal units of DNA in different cell types). To determine the extent to which BCP-ALL RT programs mirror or deviate from specific stages of normal human B-cell differentiation, we transplanted immunodeficient mice with quiescent normal human CD341 cord blood cells and obtained RT signatures of the regenerating B-lineage populations. We then compared these with RT signatures for leukemic cells from a large cohort of BCP-ALL patients with varied genetic subtypes and outcomes. The results identify BCP-ALL subtype-specific features that resemble specific stages of B-cell differentiation and features that seem to be associated with relapse. These results suggest that the genesis of BCP-ALL involves alterations in RT that reflect biologically significant and potentially clinically relevant leukemia-specific epigenetic changes.

Original languageEnglish (US)
Pages (from-to)3201-3213
Number of pages13
JournalBlood Advances
Volume3
Issue number21
DOIs
Publication statusPublished - Nov 12 2019

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ASJC Scopus subject areas

  • Hematology

Cite this

Rivera-Mulia, J. C., Sasaki, T., Trevilla-Garcia, C., Nakamichi, N., Knapp, D. J. H. F., Hammond, C. A., ... Gilbert, D. M. (2019). Replication timing alterations in leukemia affect clinically relevant chromosome domains. Blood Advances, 3(21), 3201-3213. https://doi.org/10.1182/bloodadvances.2019000641