title: Dynamic pre-BCR homodimers fine-tune autonomous survival signals in B cell precursor acute lymphoblastic leukemia.
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.
authors.affiliation: Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.|UNM Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: M Frank
authors.initials: MF
authors.lastname: Erasmus
authors.affiliation: UNM Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.|Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Ksenia
authors.initials: K
authors.lastname: Matlawska-Wasowska
authors.affiliation: Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.|UNM Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Ichiko
authors.initials: I
authors.lastname: Kinjyo
authors.affiliation: Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.|UNM Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Avanika
authors.initials: A
authors.lastname: Mahajan
authors.affiliation: UNM Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.|Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Stuart S
authors.initials: SS
authors.lastname: Winter
authors.affiliation: Sea Lane Biotechnologies, 2450 Bayshore Parkway, Mountain View, CA 94043, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.affiliation: Sea Lane Biotechnologies, 2450 Bayshore Parkway, Mountain View, CA 94043, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Horowitz
authors.affiliation: Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.|UNM Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Diane S
authors.initials: DS
authors.lastname: Lidke
authors.affiliation: Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA. bwilson@salud.unm.edu.|UNM Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Bridget S
authors.initials: BS
authors.lastname: Wilson
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000276:immunology; D006801:Humans; D054420:Pre-B Cell Receptors / Q000276:immunology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology* / Q000473:pathology; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology* / Q000473:pathology; D055503:Protein Multimerization / Q000276:immunology*; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D000072377:Syk Kinase / Q000276:immunology; D019061:src-Family Kinases / Q000276:immunology
chemical_list: C084103:BCL6 protein, human; D054420:Pre-B Cell Receptors; D051560:Proto-Oncogene Proteins c-bcl-6; C000606896:SYK protein, human; D000072377:Syk Kinase; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases