Deficiency of Bruton's tyrosine kinase in B cell precursor leukemia cells

Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13266-71. doi: 10.1073/pnas.0505196102. Epub 2005 Sep 2.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase
  • Alternative Splicing
  • Apoptosis / radiation effects
  • Base Sequence
  • Cell Differentiation
  • Cell Survival
  • Gamma Rays
  • Gene Rearrangement
  • Humans
  • Molecular Sequence Data
  • Mutation
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / enzymology*
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Protein-Tyrosine Kinases / deficiency*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / physiology
  • Tumor Cells, Cultured


  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human

Associated data

  • GENBANK/AM051275
  • GENBANK/AM051276
  • GENBANK/AM051277
  • GENBANK/AM051278
  • GENBANK/AM051279
  • GENBANK/AM051280
  • GENBANK/AM051281
  • GENBANK/AM051282
  • GENBANK/AM051283
  • GENBANK/AM051284
  • GENBANK/AM051285
  • GENBANK/AM051286