Am J Blood Res 2013;3(1):71-83
Original Article
Bruton’s tyrosine kinase mediated signaling enhances leukemogenesis in a
mouse model for chronic
lymphocytic leukemia
Laurens P Kil, Marjolein JW de Bruijn, Jennifer AC van Hulst, Anton W Langerak, Saravanan Yuvaraj, Rudi W Hendriks
Department of Pulmonary Medicine, Erasmus MC, Rotterdam, The Netherlands; Department of Immunology, Erasmus MC,
Rotterdam, The Netherlands. These authors contributed equally to this work.
Received November 6, 2012; Accepted December 11, 2012; Epub January 17, 2013; Published January 25, 2013
Abstract: In chronic lymphocytic leukemia (CLL) signals from the B cell receptor (BCR) play a major role in disease
development and progres-sion. In this light, new therapies that specifically target signaling molecules downstream of the
BCR continue to be developed. While first studies on the selective small molecule inhibitor of Bruton’s tyrosine kinase (Btk),
Ibrutinib (PCI-32765), demonstrated that Btk inhibition sensitizes CLL cells to apoptosis and alters their migratory behavior,
these studies however did not address whether Btk-mediated signaling is involved in the process of CLL leukemogenesis. To
investigate the requirement of Btk signaling for CLL development, we modulated Btk expression in the IgH.ETμ CLL mouse
model, which is based on sporadic expression of the simian oncovirus SV40 T-antigen in mature B cells. To this end, we
crossed IgH.ETμ mice on a Btk-deficient background or introduced a human Btk transgene (CD19-hBtk). Here we show that
Btk deficiency fully abrogates CLL formation in IgH.ETμ mice, and that leukemias formed in Btk haplo-insufficient mice
selectively expressed the wild-type Btk allele on their active X chromosome. Conversely, Btk overexpression accelerated CLL
onset, increased mortality, and was associated with selection of non-stereotypical BCRs into CLL clones. Taken together,
these data show that Btk expression represents an absolute prerequisite for CLL development and that Btk mediated
signaling enhances leukemogenesis in mice. We therefore conclude that in CLL Btk expression levels set the threshold for
malignant transformation. (AJBR1211001).
Keywords: Chronic lymphocytic leukemia (CLL), bruton’s tyrosine kinase (Btk), B cell receptor signaling
Address all correspondence to:
Dr. Rudi W Hendriks
Department of Pulmonary Medicine
Room Ee2251a, Erasmus MC Rotterdam
PO Box 2040, NL 3000 CA Rotterdam, The Netherlands.
Phone: ++31-10-7043700; Fax: ++31-10-7044728
E-mail: r.hendriks@erasmusmc.nl
Original Article
Bruton’s tyrosine kinase mediated signaling enhances leukemogenesis in a
mouse model for chronic
lymphocytic leukemia
Laurens P Kil, Marjolein JW de Bruijn, Jennifer AC van Hulst, Anton W Langerak, Saravanan Yuvaraj, Rudi W Hendriks
Department of Pulmonary Medicine, Erasmus MC, Rotterdam, The Netherlands; Department of Immunology, Erasmus MC,
Rotterdam, The Netherlands. These authors contributed equally to this work.
Received November 6, 2012; Accepted December 11, 2012; Epub January 17, 2013; Published January 25, 2013
Abstract: In chronic lymphocytic leukemia (CLL) signals from the B cell receptor (BCR) play a major role in disease
development and progres-sion. In this light, new therapies that specifically target signaling molecules downstream of the
BCR continue to be developed. While first studies on the selective small molecule inhibitor of Bruton’s tyrosine kinase (Btk),
Ibrutinib (PCI-32765), demonstrated that Btk inhibition sensitizes CLL cells to apoptosis and alters their migratory behavior,
these studies however did not address whether Btk-mediated signaling is involved in the process of CLL leukemogenesis. To
investigate the requirement of Btk signaling for CLL development, we modulated Btk expression in the IgH.ETμ CLL mouse
model, which is based on sporadic expression of the simian oncovirus SV40 T-antigen in mature B cells. To this end, we
crossed IgH.ETμ mice on a Btk-deficient background or introduced a human Btk transgene (CD19-hBtk). Here we show that
Btk deficiency fully abrogates CLL formation in IgH.ETμ mice, and that leukemias formed in Btk haplo-insufficient mice
selectively expressed the wild-type Btk allele on their active X chromosome. Conversely, Btk overexpression accelerated CLL
onset, increased mortality, and was associated with selection of non-stereotypical BCRs into CLL clones. Taken together,
these data show that Btk expression represents an absolute prerequisite for CLL development and that Btk mediated
signaling enhances leukemogenesis in mice. We therefore conclude that in CLL Btk expression levels set the threshold for
malignant transformation. (AJBR1211001).
Keywords: Chronic lymphocytic leukemia (CLL), bruton’s tyrosine kinase (Btk), B cell receptor signaling
Address all correspondence to:
Dr. Rudi W Hendriks
Department of Pulmonary Medicine
Room Ee2251a, Erasmus MC Rotterdam
PO Box 2040, NL 3000 CA Rotterdam, The Netherlands.
Phone: ++31-10-7043700; Fax: ++31-10-7044728
E-mail: r.hendriks@erasmusmc.nl
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