Research ArticleImmunology

Dynamic pre-BCR homodimers fine-tune autonomous survival signals in B cell precursor acute lymphoblastic leukemia

Sci. Signal.  29 Nov 2016:
Vol. 9, Issue 456, pp. ra116
DOI: 10.1126/scisignal.aaf3949

You are currently viewing the abstract.

View Full Text

Via your Institution

Log in through your institution

Log in through your institution


Monitoring pre-BCR dynamics

Signaling by the pre–B cell receptor (pre-BCR) complex, an immature form of the BCR, ensures the development and survival of B cell progenitors. Erasmus et al. used single-particle tracking to monitor the movements of differentially labeled pre-BCRs in cells from patients with B cell precursor acute lymphoblastic leukemia (BCP-ALL). The pre-BCRs frequently formed ligand-independent, transient homotypic interactions that correlated with cellular survival signaling. In contrast, the pre-BCR ligand galectin-1 induced the formation of large aggregates of immobile receptors. Interfering with the dynamic homotypic interactions between the pre-BCRs rendered the BCP-ALL cells more sensitive to cell death induced by chemotherapy, suggesting that disrupting pre-BCR dynamics may help to make chemotherapy more effective.

Abstract

The pre–B cell receptor (pre-BCR) is an immature form of the BCR critical for early B lymphocyte development. It is composed of the membrane-bound immunoglobulin (Ig) heavy chain, surrogate light chain components, and the signaling subunits Igα and Igβ. We developed monovalent quantum dot (QD)–labeled probes specific for Igβ to study the behavior of pre-BCRs engaged in autonomous, ligand-independent signaling in live B cells. Single-particle tracking revealed that QD-labeled pre-BCRs engaged in transient, but frequent, homotypic interactions. Receptor motion was correlated at short separation distances, consistent with the formation of dimers and higher-order oligomers. Repeated encounters between diffusing pre-BCRs appeared to reflect transient co-confinement in plasma membrane domains. In human B cell precursor acute lymphoblastic leukemia (BCP-ALL) cells, we showed that frequent, short-lived, homotypic pre-BCR interactions stimulated survival signals, including expression of BCL6, which encodes a transcriptional repressor. These survival signals were blocked by inhibitory monovalent antigen-binding antibody fragments (Fabs) specific for the surrogate light chain components of the pre-BCR or by inhibitors of the tyrosine kinases Lyn and Syk. For comparison, we evaluated pre-BCR aggregation mediated by dimeric galectin-1, which has binding sites for carbohydrate and for the surrogate light chain λ5 component. Galectin-1 binding resulted in the formation of large, highly immobile pre-BCR aggregates, which was partially relieved by the addition of lactose to prevent the cross-linking of galectin-BCR complexes to other glycosylated membrane components. Analysis of the pre-BCR and its signaling partners suggested that they could be potential targets for combination therapy in BCP-ALL.

View Full Text

Related Content