Deficiency of Bruton's tyrosine kinase in B cell precursor leukemia cells.
Bruton's tyrosine kinase (BTK) deficiency results in a differentiation block at the pre-B cell stage. Likewise, acute lymphoblastic leukemia cells are typically arrested at early stages of B cell development. We therefore investigated BTK function in B cell precursor leukemia cells carrying a BCR-ABL1, E2A-PBX1, MLL-AF4, TEL-AML1, or TEL-PDGFRB gene rearrangement. Although somatic mutations of the BTK gene are rare in B cell precursor leukemia cells, we identified kinase-deficient splice variants of BTK throughout all leukemia subtypes. Unlike infant leukemia cells carrying an MLL-AF4 gene rearrangement, where expression of full-length BTK was detectable in only four of eight primary cases, in leukemia cells harboring other fusion genes full-length BTK was typically coexpressed with kinase-deficient variants. As shown by overexpression experiments, kinase-deficient splice variants can act as a dominant-negative BTK in that they suppress BTK-dependent differentiation and pre-B cell receptor responsiveness of the leukemia cells. On the other hand, induced expression of full-length BTK rendered the leukemia cells particularly sensitive to apoptosis. Comparing BTK expression in surviving or preapoptotic leukemia cells after 10-Gy gamma radiation, we observed selective survival of leukemia cells that exhibit expression of dominant-negative BTK forms. These findings indicate that lack of BTK expression or expression of dominant-negative splice variants in B cell precursor leukemia cells can (i) inhibit differentiation beyond the pre-B cell stage and (ii) protect from radiation-induced apoptosis.
Feldhahn
Niklas
N
Laboratory for Molecular Stem Cell Biology, Institute for Transplantation Diagnostics and Cell Therapeutics, and Department of Pediatric Hematology and Oncology, Children's Hospital, Heinrich-Heine-Universität, 40225 Düsseldorf, Germany.
Río
Paula
P
Soh
Bonaventure Ndikung Bejeng
BN
Liedtke
Stefanie
S
Sprangers
Mieke
M
Klein
Florian
F
Wernet
Peter
P
Jumaa
Hassan
H
Hofmann
Wolf-Karsten
WK
Hanenberg
Helmut
H
Rowley
Janet D
JD
Müschen
Markus
M
D000077329:Agammaglobulinaemia Tyrosine Kinase; D017398:Alternative Splicing; D017209:Apoptosis / Q000528:radiation effects; D001483:Base Sequence; D002454:Cell Differentiation; D002470:Cell Survival; D005720:Gamma Rays; D015321:Gene Rearrangement; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D014407:Tumor Cells, Cultured
D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human