title: Deficiency of the adaptor SLP-65 in pre-B-cell acute lymphoblastic leukaemia.
abstract: Acute lymphoblastic leukaemia (ALL) is the commonest form of childhood malignancy, and most cases arise from B-cell clones arrested at the pre-B-cell stage of differentiation. The molecular events that arrest pre-B-cell differentiation in the leukaemic pre-B cells have not been well characterized. Here we show that the differentiation regulator SLP-65 (an adaptor protein also called BLNK or BASH) inhibits pre-B-cell leukaemia in mice. Reconstitution of SLP-65 expression in a SLP-65-/- pre-B-cell line led to enhanced differentiation in vitro and prevented the development of pre-B-cell leukaemia in immune-deficient mice. Tyrosine 96 of SLP-65 was required for this activity. The murine SLP-65-/- pre-B-cell leukaemia resembles human childhood pre-B ALL. Indeed, 16 of the 34 childhood pre-B ALL samples that were tested showed a complete loss or drastic reduction of SLP-65 expression. This loss is probably due to the incorporation of alternative exons into SLP-65 transcripts, leading to premature stop codons. Thus, the somatic loss of SLP-65 and the accompanying block in pre-B-cell differentiation might be one of the primary causes of childhood pre-B ALL.
authors.affiliation: Biologie III, University of Freiburg and Max Planck Institute for Immunobiology, D-79108 Freiburg, Germany. jumaa@immunbio.mpg.de
authors.forename: Hassan
authors.initials: H
authors.lastname: Jumaa
authors.forename: Lukas
authors.initials: L
authors.lastname: Bossaller
authors.forename: Karina
authors.initials: K
authors.lastname: Portugal
authors.forename: Bettina
authors.initials: B
authors.lastname: Storch
authors.forename: Michael
authors.initials: M
authors.lastname: Lotz
authors.forename: Alexandra
authors.initials: A
authors.lastname: Flemming
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.forename: Ville
authors.initials: V
authors.lastname: Postila
authors.forename: Pekka
authors.initials: P
authors.lastname: Riikonen
authors.forename: Jukka
authors.initials: J
authors.lastname: Pelkonen
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Niemeyer
authors.forename: Michael
authors.initials: M
authors.lastname: Reth
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005091:Exons / Q000235:genetics; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007223:Infant; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010750:Phosphoproteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; D002352:Carrier Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase