Mimicry of a constitutively active pre-B cell receptor in acute lymphoblastic leukemia cells.
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.
Feldhahn
Niklas
N
Laboratory for Molecular Stem Cell Biology, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany.
Klein
Florian
F
Mooster
Jana L
JL
Hadweh
Paul
P
Sprangers
Mieke
M
Wartenberg
Maria
M
Bekhite
Mohamed M
MM
Hofmann
Wolf-Karsten
WK
Herzog
Sebastian
S
Jumaa
Hassan
H
Rowley
Janet D
JD
Müschen
Markus
M
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
D008562:Membrane Glycoproteins; D054420:Pre-B Cell Receptors; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases