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

Niklas Feldhahn, Paula Río, Bonaventure Ndikung Bejeng Soh, Stefanie Liedtke, Mieke Sprangers, Florian Klein, Peter Wernet, Hassan Jumaa, Wolf Karsten Hofmann, Helmut Hanenberg, Janet D. Rowley, Markus Müschen

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

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 γ 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.

Original languageEnglish (US)
Pages (from-to)13266-13271
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number37
DOIs
StatePublished - Sep 13 2005
Externally publishedYes

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B-Cell Leukemia
Leukemia
B-Lymphoid Precursor Cells
Phosphotransferases
Gene Rearrangement
Agammaglobulinaemia tyrosine kinase
Pre-B Cell Receptors
Apoptosis
Platelet-Derived Growth Factor beta Receptor
Radiation Dosage
Gene Fusion
Precursor Cell Lymphoblastic Leukemia-Lymphoma

Keywords

  • Apoptosis
  • Differentiation block
  • Pre-B cell receptor

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Feldhahn, N., Río, P., Soh, B. N. B., Liedtke, S., Sprangers, M., Klein, F., ... Müschen, M. (2005). Deficiency of Bruton's tyrosine kinase in B cell precursor leukemia cells. Proceedings of the National Academy of Sciences of the United States of America, 102(37), 13266-13271. https://doi.org/10.1073/pnas.0505196102

Deficiency of Bruton's tyrosine kinase in B cell precursor leukemia cells. / Feldhahn, Niklas; Río, Paula; Soh, Bonaventure Ndikung Bejeng; Liedtke, Stefanie; Sprangers, Mieke; Klein, Florian; Wernet, Peter; Jumaa, Hassan; Hofmann, Wolf Karsten; Hanenberg, Helmut; Rowley, Janet D.; Müschen, Markus.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 37, 13.09.2005, p. 13266-13271.

Research output: Contribution to journalArticle

Feldhahn, N, Río, P, Soh, BNB, Liedtke, S, Sprangers, M, Klein, F, Wernet, P, Jumaa, H, Hofmann, WK, Hanenberg, H, Rowley, JD & Müschen, M 2005, 'Deficiency of Bruton's tyrosine kinase in B cell precursor leukemia cells', Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 37, pp. 13266-13271. https://doi.org/10.1073/pnas.0505196102
Feldhahn, Niklas ; Río, Paula ; Soh, Bonaventure Ndikung Bejeng ; Liedtke, Stefanie ; Sprangers, Mieke ; Klein, Florian ; Wernet, Peter ; Jumaa, Hassan ; Hofmann, Wolf Karsten ; Hanenberg, Helmut ; Rowley, Janet D. ; Müschen, Markus. / Deficiency of Bruton's tyrosine kinase in B cell precursor leukemia cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 37. pp. 13266-13271.
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AU - Sprangers, Mieke

AU - Klein, Florian

AU - Wernet, Peter

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AB - 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 γ 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.

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