title: Mimicry of a constitutively active pre-B cell receptor in acute lymphoblastic leukemia cells.
abstract: Pre-B cells undergo apoptosis unless they are rescued by pre-B cell receptor-dependent survival signals. We previously showed that the BCR-ABL1 kinase that is expressed in pre-B lymphoblastic leukemia bypasses selection for pre-B cell receptor-dependent survival signals. Investigating possible interference of BCR-ABL1 with pre-B cell receptor signaling, we found that neither SYK nor SLP65 can be phosphorylated in response to pre-B cell receptor engagement. Instead, Bruton's tyrosine kinase (BTK) is constitutively phosphorylated by BCR-ABL1. Activated BTK is essential for survival signals that otherwise would arise from the pre-B cell receptor, including activation of PLCgamma1, autonomous Ca2+ signaling, STAT5-phosphorylation, and up-regulation of BCLX(L). Inhibition of BTK activity specifically induces apoptosis in BCR-ABL1+ leukemia cells to a similar extent as inhibition of BCR-ABL1 kinase activity itself. However, BCR-ABL1 cannot directly bind to full-length BTK. Instead, BCR-ABL1 induces the expression of a truncated splice variant of BTK that acts as a linker between the two kinases. As opposed to full-length BTK, truncated BTK lacks kinase activity yet can bind to BCR-ABL1 through its SRC-homology domain 3. Acting as a linker, truncated BTK enables BCR-ABL1-dependent activation of full-length BTK, which initiates downstream survival signals and mimics a constitutively active pre-B cell receptor.
authors.affiliation: Laboratory for Molecular Stem Cell Biology, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Niklas
authors.initials: N
authors.lastname: Feldhahn
authors.forename: Florian
authors.initials: F
authors.lastname: Klein
authors.forename: Jana L
authors.initials: JL
authors.lastname: Mooster
authors.forename: Paul
authors.initials: P
authors.lastname: Hadweh
authors.forename: Mieke
authors.initials: M
authors.lastname: Sprangers
authors.forename: Maria
authors.initials: M
authors.lastname: Wartenberg
authors.forename: Mohamed M
authors.initials: MM
authors.lastname: Bekhite
authors.forename: Wolf-Karsten
authors.initials: WK
authors.lastname: Hofmann
authors.forename: Sebastian
authors.initials: S
authors.lastname: Herzog
authors.forename: Hassan
authors.initials: H
authors.lastname: Jumaa
authors.forename: Janet D
authors.initials: JD
authors.lastname: Rowley
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D020013:Calcium Signaling; D045744:Cell Line, Tumor; D002470:Cell Survival; D002648:Child; D002675:Child, Preschool; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D008875:Middle Aged; D018716:Molecular Mimicry; D054420:Pre-B Cell Receptors; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell
chemical_list: D008562:Membrane Glycoproteins; D054420:Pre-B Cell Receptors; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases