Variable Retention of Differentiation-specific DNA Replication Timing in Human Pediatric Leukemia

Rivera-Mulia, J. C.; Sasaki, T.; Trevilla-Garcia, C.; Nakamichi, N.; Knapp, D. J. H. F.; Hammond, C.; Chang, B.; Tyner, J. W.; Devidas, M.; Zimmerman, J.; Klein, K.; Somasundaram, V.; Druker, B.; Gruber, T.; Koren, A.; Eaves, C. J.; Gilbert, D. M.

doi:10.1101/549196

bioRxiv · 10.1101/549196

Variable Retention of Differentiation-specific DNA Replication Timing in Human Pediatric Leukemia

Rivera-Mulia, J. C.·Sasaki, T.·Trevilla-Garcia, C.·Nakamichi, N.·Knapp, D. J. H. F.·Hammond, C.·Chang, B.·Tyner, J. W.·Devidas, M.·Zimmerman, J.·Klein, K.·Somasundaram, V.·Druker, B.·Gruber, T.·Koren, A.·Eaves, C. J.·Gilbert, D. M.

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Abstract

Human B-lineage 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 BCP-ALL cells display unique and clonally heritable DNA-replication timing (RT) programs; i.e., programs describing the variable order of replication 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. The results identify BCP-ALL subtype-specific features that resemble specific stages of B-cell differentiation and features that appear associated with relapse. These results suggest the genesis of BCP-ALL involves alterations in RT that reflect clinically relevant leukemia-specific genetic and/or epigenetic changes. SUMMARYGenome-wide DNA replication timing profiles of >100 pediatric leukemic samples and normally differentiating human B-lineage cells isolated from xenografted immunodeficient mice were generated. Comparison of these identified potentially clinically relevant features that both match and deviate from the normal profiles.

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Rivera-Mulia, J. C., Sasaki, T., Trevilla-Garcia, C., Nakamichi, N., Knapp, D. J. H. F., Hammond, C., Chang, B., Tyner, J. W., Devidas, M., Zimmerman, J., Klein, K., Somasundaram, V., Druker, B., Gruber, T., Koren, A., Eaves, C. J., Gilbert, D. M.. 2019-02-13. Variable Retention of Differentiation-specific DNA Replication Timing in Human Pediatric Leukemia. https://doi.org/10.1101/549196

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