title: SLP65 deficiency results in perpetual V(D)J recombinase activity in pre-B-lymphoblastic leukemia and B-cell lymphoma cells.
abstract: Perpetual V(D)J recombinase activity involving multiple DNA double-strand break events in B-cell lineage leukemia and lymphoma cells may introduce secondary genetic aberrations leading towards malignant progression. Here, we investigated defective negative feedback signaling through the (pre-) B-cell receptor as a possible reason for deregulated V(D)J recombinase activity in B-cell malignancy. On studying 28 cases of pre-B-lymphoblastic leukemia and 27 B-cell lymphomas, expression of the (pre-) B-cell receptor-related linker molecule SLP65 (SH2 domain-containing lymphocyte protein of 65 kDa) was found to be defective in seven and five cases, respectively. SLP65 deficiency correlates with RAG1/2 expression and unremitting V(H) gene rearrangement activity. Reconstitution of SLP65 expression in SLP65-deficient leukemia and lymphoma cells results in downregulation of RAG1/2 expression and prevents both de novo V(H)-DJ(H) rearrangements and secondary V(H) replacement. We conclude that iterative V(H) gene rearrangement represents a frequent feature in B-lymphoid malignancy, which can be attributed to SLP65 deficiency in many cases.
authors.affiliation: Laboratory for Molecular Stem Cell Biology, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Sprangers
authors.forename: N
authors.initials: N
authors.lastname: Feldhahn
authors.forename: S
authors.initials: S
authors.lastname: Liedtke
authors.forename: H
authors.initials: H
authors.lastname: Jumaa
authors.forename: R
authors.initials: R
authors.lastname: Siebert
authors.forename: M
authors.initials: M
authors.lastname: Müschen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001483:Base Sequence; D002051:Burkitt Lymphoma / Q000201:enzymology / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D004249:DNA Damage; D015321:Gene Rearrangement; D005803:Genes, Immunoglobulin; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics*; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000172:deficiency* / Q000235:genetics*; D017384:Sequence Deletion; D045567:VDJ Recombinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; D002352:Carrier Proteins; D010750:Phosphoproteins; D045567:VDJ Recombinases