Pre-B-cell leukemias in Btk/Slp65-deficient mice arise independently of ongoing V(D)J recombination activity
The adapter protein Slp65 and Bruton's tyrosine kinase (Btk) are key components of the precursor-B (pre-B) cell receptor (pre-BCR) signaling pathway. Slp65-deficient mice spontaneously develop pre-B-cell leukemia, expressing high levels of the pre-BCR on their cell surface. As leukemic Slp65-deficient pre-B cells express the recombination activating genes (Rag)1 and Rag2, and manifest ongoing immunoglobulin (Ig) light-chain rearrangement, it has been hypothesized that deregulated recombinase activity contributes to malignant transformation. In this report, we investigated whether Rag-induced DNA damage is involved in oncogenic transformation of Slp65-deficient B cells. We employed Btk/Slp65 double-deficient mice carrying an autoreactive 3-83μδ BCR transgene. When developing B cells in their bone marrow express this BCR, the V(D)J recombination machinery will be activated, allowing for secondary Ig light-chain gene rearrangements to occur. This phenomenon, called receptor editing, will rescue autoreactive B cells from apoptosis. We observed that 3-83μδ transgenic Btk/Slp65 double-deficient mice developed B-cell leukemias expressing both the 3-83μδ BCR and the pre-BCR components λ5/VpreB. Importantly, such leukemias were found at similar frequencies in mice concomitantly deficient for Rag1 or the non-homologous end-joining factor DNA-PKcs. We therefore conclude that malignant transformation of Btk/Slp65 double-deficient pre-B cells is independent of deregulated V(D)J recombination activity.Leukemia advance online publication, 29 October 2010; doi:10.1038/leu.2010.246.
|Persistent URL||dx.doi.org/10.1038/leu.2010.246, hdl.handle.net/1765/21635|
|Note||Article in press - dd November 2010|
Ta, T.B.V., Haan, A.B., de Bruijn, M.J.W., Dingjan, G.M., & Hendriks, R.W.. (2010). Pre-B-cell leukemias in Btk/Slp65-deficient mice arise independently of ongoing V(D)J recombination activity. Leukemia, 25(1), 48–56. doi:10.1038/leu.2010.246