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.
Bibliographical noteFunding Information:
The authors thank R. Didier for expert help with flow cytometry, and M. Hale and G. Edin and the British Columbia Cancer Agency Stem Cell Assay Laboratory staff for technical assistance in CB cell processing and animal irradiations. This work was supported by National Institutes of Health (NIH), National Cancer Institute (NCI) grant R21 CA161666 and NIH, National Institute of General Medical Sciences grant R01 GM083337, and a Margaret and Mary Pfeiffer Professorship for Cancer Research (D.M.G.), a Terry Fox Foundation New Frontiers Program Project grant, and Canadian Cancer Research Society Research Institute grants (C.J.E.). D.J.H.F.K. held a Canadian Institutes of Health Research (CIHR) Vanier Scholarship, and C.A.H. held a CIHR Frederick Banting and Charles Best Doctoral Scholarship. Children’s Oncology Group trials were supported by NIH, NCI grants U10 CA98543, U10 CA98413, U10 CA180886, 1U24-CA196173, and U10 CA180899, and by St. Baldrick’s Foundation.
© 2019 by The American Society of Hematology
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