DNA damage signals repress SYK in early B cells to facilitate maturation and limit leukemic transformation

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Presentation Time: 10:15 AM - 10:30 AM
Abstract ID: 4235 -B

Presenting Author:
Haley A Schmidt , Graduate Student at Washington Univ. Sch. of Med., St. Louis

Abstract:

The pre-B checkpoint is a critical stage of B cell development that segregates clonal expansion and assembly of a mature B cell receptor. The pre-B cell receptor (pre-BCR) coordinates proliferation and immunoglobulin light chain (Igl) gene rearrangement. Igl rearrangement proceeds by RAG-mediated DNA double-stranded breaks (DSBs) which occur only in G1-arrested cells. Pathways opposing pre-BCR proliferative signaling prevent pre-B cells with RAG DSBs from prematurely re-entering cell cycle. Dysregulation of this checkpoint impairs B cell differentiation and drives leukemic transformation.

We have identified that RAG DSBs trigger DNA damage responses (DDRs) inducing activation of the SPIC/BCLAF1 transcriptional repressor complex, which suppresses pre-BCR signaling. Using novel mouse models to characterize pre-BCR and DDR signals in vivo, we find that SYK, a pro-proliferative kinase activated by pre-BCR, is repressed by RAG-mediated DSBs, and that DDR signaling dynamically changes in pre-B cells. Loss of BCLAF1 disrupts the developmental progression of pre-B cells and alters kinetics of DDR and pre-BCR signals. Further, loss of BCLAF1 results in expansion of aberrant B cell populations. This study establishes a novel system for quantitating DDRs in pre-B cells in vivo and for assessing dynamic signaling at the pre-B checkpoint. We show that RAG-mediated DDRs integrate with B cell developmental programs to maintain pre-B cell checkpoint and promote normal maturation.