TY - JOUR

T1 - A novel BLK-induced tumor model

AU - Petersen, David Leander

AU - Berthelsen, Jens

AU - Willerslev-Olsen, Andreas

AU - Fredholm, Simon

AU - Dabelsteen, Sally

AU - Bonefeld, Charlotte Menné

AU - Geisler, Carsten

AU - Woetmann, Anders

PY - 2017/7

Y1 - 2017/7

N2 - B-lymphoid tyrosine kinase (BLK) is a non-receptor tyrosine kinase belonging to the SRC family kinases. BLK is known to be functionally involved in B-cell receptor signaling and B-cell development. New evidence suggests that B-lymphoid tyrosine kinase is ectopically expressed and is a putative oncogene in cutaneous T-cell lymphoma and other T-cell malignancies. However, little is known about the role of BLK in lymphomagenesis, and the oncogenic function seems to depend on the cellular context. Importantly, BLK is also ectopically expressed in other hematological and multiple non-hematological malignancies including breast, kidney, and lung cancers, suggesting that BLK could be a new potential target for therapy. Here, we studied the oncogenic potential of human BLK. We found that engrafted Ba/F3 cells stably expressing constitutive active human BLK formed tumors in mice, whereas neither Ba/F3 cells expressing wild type BLK nor non-transfected Ba/F3 cells did. Inhibition of BLK with the clinical grade and broadly reacting SRC family kinase inhibitor dasatinib inhibited growth of BLK-induced tumors. In conclusion, our study provides evidence that human BLK is a true proto-oncogene capable of inducing tumors, and we demonstrate a novel BLK activity-dependent tumor model suitable for studies of BLK-driven lymphomagenesis and screening of novel BLK inhibitors in vivo.

AB - B-lymphoid tyrosine kinase (BLK) is a non-receptor tyrosine kinase belonging to the SRC family kinases. BLK is known to be functionally involved in B-cell receptor signaling and B-cell development. New evidence suggests that B-lymphoid tyrosine kinase is ectopically expressed and is a putative oncogene in cutaneous T-cell lymphoma and other T-cell malignancies. However, little is known about the role of BLK in lymphomagenesis, and the oncogenic function seems to depend on the cellular context. Importantly, BLK is also ectopically expressed in other hematological and multiple non-hematological malignancies including breast, kidney, and lung cancers, suggesting that BLK could be a new potential target for therapy. Here, we studied the oncogenic potential of human BLK. We found that engrafted Ba/F3 cells stably expressing constitutive active human BLK formed tumors in mice, whereas neither Ba/F3 cells expressing wild type BLK nor non-transfected Ba/F3 cells did. Inhibition of BLK with the clinical grade and broadly reacting SRC family kinase inhibitor dasatinib inhibited growth of BLK-induced tumors. In conclusion, our study provides evidence that human BLK is a true proto-oncogene capable of inducing tumors, and we demonstrate a novel BLK activity-dependent tumor model suitable for studies of BLK-driven lymphomagenesis and screening of novel BLK inhibitors in vivo.

KW - Animals

KW - B-Lymphocytes

KW - Carcinogenesis

KW - Cell Line, Tumor

KW - Disease Models, Animal

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Lymphocyte Activation

KW - Lymphoma, T-Cell, Cutaneous

KW - Mice

KW - Signal Transduction

KW - Xenograft Model Antitumor Assays

KW - src-Family Kinases

KW - Journal Article

U2 - 10.1177/1010428317714196

DO - 10.1177/1010428317714196

M3 - Journal article

C2 - 28670978

VL - 39

JO - Tumor Biology

JF - Tumor Biology

SN - 1010-4283

IS - 7

ER -