Replication timing alterations in leukemia affect clinically relevant chromosome domains

Rivera-Mulia JC, Sasaki T, Trevilla-Garcia C, Nakamichi N, Knapp DJHF, Hammond CA, Chang BH, Tyner JW, Devidas M, Zimmerman J, Klein KN, Somasundaram V, Druker BJ, Gruber TA, Koren A, Eaves CJ, Gilbert DM. Replication timing alterations in leukemia affect clinically relevant chromosome domains. Blood Adv. 2019 Nov 12;3(21):3201-3213. doi: 10.1182/bloodadvances.2019000641. PubMed PMID: 31698451; PubMed Central PMCID: PMC6855107.

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.