Replication timing alterations in leukemia affect clinically relevant chromosome domains

• Published in: Blood advances Vol. 3; no. 21; pp. 3201 - 3213
• Main Authors: Rivera-Mulia, Juan Carlos, Sasaki, Takayo, Trevilla-Garcia, Claudia, Nakamichi, Naoto, Knapp, David J. H.F., Hammond, Colin A., Chang, Bill H., Tyner, Jeffrey W., Devidas, Meenakshi, Zimmerman, Jared, Klein, Kyle N., Somasundaram, Vivek, Druker, Brian J., Gruber, Tanja A., Koren, Amnon, Eaves, Connie J., Gilbert, David M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.11.2019; American Society of Hematology; Elsevier
• Subjects: Hematopoiesis and Stem Cells
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2019000641

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 CD34+ 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. •DNA replication timing of >100 pediatric leukemic samples identified BCP-ALL subtype-specific genome alteration signatures.•Comparative analyses identified features of specific stages of B-cell differentiation and potential associations with clinical outcome. [Display omitted]