Abstract 4609

Abnormal temporal control of replication (“replication timing”) is a universal hallmark of cancer, but the significance of this relationship is not understood. During normal development, changes in replication timing are regulated in defined chromosomal units (“replication domains”) of 400–800 kb, with late replication generally associated with stable gene silencing. We have performed genome-wide replication timing mapping on pediatric acute leukemias and identified patterns of replication-timing mis-regulation (“leukemia fingerprints”) in common across multiple types of pediatric leukemia (“multi-lineage fingerprints”), as well as those linked to specific subtypes of acute leukemia and patient-specific fingerprints. Most of the mis-regulated regions are not associated with copy number variation or translocations and correspond to many of the same domains whose replication timing is regulated during normal development. The existence of multi-lineage fingerprints suggests an early origin of their mis-regulation while type-specific and patient-specific fingerprints suggest that mis-regulation continues to occur downstream of the initiating event. Our hypothesis is that there exists an hierarchy of replication-timing mis-regulation, initiating with frozen vestiges of normal hematopoiesis that are inappropriately maintained, followed by additional changes that evolve as the tumor differentiates. These changes may then affect the ability of downstream lineages to activate or silence genes. Since chromatin is assembled at the replication fork, and different types of chromatin are assembled at different times during S phase, changes in replication timing likely contribute to domain-wide changes in chromatin structure, similar to those observed in long range epigenetic silencing (LRES). In fact, we find that genes within leukemia fingerprint domains are significantly enriched for those transcribed during hematopoiesis and/or mis-regulated in cancers. Replication timing is an exceptionally stable epigenetic property that is not easily disturbed by loss or mis-expression of single master regulators of cell fate and is not directly related to transcription, but rather to the stability of gene silencing. Hence, events occurring early in hematopoiesis could have profound effects on the activation of transcriptional programs in downstream lineages. Elucidating the genesis and genealogy of leukemia-specific replication timing fingerprints and their relationship to transcriptional control will be fundamental to understanding their link to the development of acute leukemias.

Disclosures:

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.

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