A Cell-type Specific Checkpoint Limits Proliferation in Early B Cells

Background

Pre-B acute lymphoblastic leukemia (pre-B ALL) is the most common malignancy in children. However, remarkably little is known about the molecular basis of the initiation and maintenance of this leukemia. In pre-B ALL, B cell development is arrested at an early developmental stage and the leukemic blasts hijack normal developmental signaling to support their survival and proliferation.

A subset of high-risk ALL is dependent on pre-B cell receptor (pre-BCR) signaling for proliferation and survival. In developing B cells, the pre-BCR coordinates essential programs for B cell maturation. How pre-BCR signaling is tuned to direct normal development and simultaneously prevent leukemic transformation is unknown. We have identified a novel feedback circuit that inhibits pre-BCR signaling and limits pre-B cell proliferation.

Project Goal

The goal of this project is to understand how this regulatory pathway is coordinated in early B cells. Our preliminary work has demonstrated that signals from DNA breaks suppress expression of SYK, a key signaling protein downstream of the pre-BCR. This pathway functions independent of p53, a canonical tumor suppressor. We hypothesize that this DNA break dependent reduction in SYK is an important checkpoint for maintaining genomic stability, directing normal maturation and suppressing leukemic transformation.

Experiments will investigate the mechanisms by which DNA damage responses modulate SYK activity in developing B cells. Understanding these processes will provide new insights into the initiation and maintenance of leukemia. This pathway is an attractive target for new therapies as modulation of these signals could suppress proliferation of leukemic cells, including those deficient in p53.