Pre-B-cell leukemia spontaneously develops in BLNK-deficient mice, and pre-Bcell acute lymphoblastic leukemia cells in children often lack BLNK protein expression, demonstrating that BLNK functions as a tumor suppressor. However, the mechanism by which BLNK suppresses pre-B-cell leukemia, as well as the identification of other genetic alterations that collaborate with BLNK deficiency to cause leukemogenesis, are still unknown. Here, we demonstrate that the JAK3/STAT5 signaling pathway is constitutively activated IntroductionIn early B-cell development, successful rearrangement of the immunoglobulin (Ig) heavy (H) chain gene in progenitor B cells results in surface expression of H chain in the form of a complex with VpreB and 5, called the pre-B-cell receptor (pre-BCR), resulting in differentiation to the pre-B-cell stage. Transient surface expression of the pre-BCR triggers rapid cell-cycle progression, thereby forming a large pre-B-cell population, and ultimately promoting development toward the small pre-B-cell and immature B-cell stages. 1,2 Pre-B cells in the absence of signals derived from the pre-BCR undergo apoptotic cell death. 3 Signal transduction from the pre-BCR requires recruitment and activation of the Syk tyrosine kinase. 4 Activated Syk phosphorylates several downstream signaling elements, including BLNK (also known as SLP-65 or BASH).BLNK is a pivotal adapter protein in signal transduction from the pre-BCR and BCR. BLNK contains multiple tyrosine phosphorylation sites that provide binding sites for key signaling proteins such as PLC␥, Btk, and Vav. 5 BLNK gene mutations cause a complete block in B-cell development at the pro-B-cell to pre-Bcell transition in humans. 6 In BLNK-null mutant mice the developmental block is partial, resulting in the accumulation of pre-BCR ϩ large pre-B cells in the bone marrow and a reduction of mature B cells in the periphery. 7 We and others previously reported that 5% to 10% of BLNK Ϫ/Ϫ mice spontaneously develop pre-B-cell leukemia at 4 to 20 weeks of age. [7][8][9] Pre-B-cell-derived acute lymphoblastic leukemia (pre-B-ALL) is the most common type of leukemia in children. 10 Interestingly, one study reported that 50% of the pediatric B-ALL cases they investigated had lost BLNK protein expression, 11 although other studies reported a lower frequency. 12,13 Thus, it has been proposed that BLNK functions as a tumor suppressor, but the molecular mechanisms by which it exerts tumor suppressor activity are still unknown. Because tumorigenesis is a multistep process requiring sequential changes in various genes, 14 it is unlikely that BLNK deficiency is sufficient to initiate leukemogenesis.Combined deficiency of BLNK and Btk results in a more severe developmental block at the pre-B-cell stage 15 and a higher incidence of pre-B-cell leukemia compared with mice deficient in either gene alone, [7][8][9]16 suggesting that the developmental block is one of the tumor-promoting factors. However, mice that cannot express the pre-BCR, such as MT or RAG-deficient mice, exhibi...
The data identify Debio-0719 as a drug candidate with metastasis suppressor activity, inducing dormancy at secondary tumor sites.
Metastasis of cancer cells is multi-step process and dissemination is an initial step. Here we report a tamoxifen-controllable Twist1a-ERT2 transgenic zebrafish line as a new animal model for metastasis research, and demonstrate that this model can serve as a novel platform for discovery of antimetastasis drugs targeting metastatic dissemination of cancer cells. By crossing Twist1a-ERT2 with xmrk (a homolog of hyperactive form of EGFR) transgenic zebrafish, which develops hepatocellular carcinoma, approximately 80% of the double transgenic zebrafish showed spontaneous cell dissemination of mCherry-labeled hepatocytes from the liver to the entire abdomen region and the tail region. The dissemination is accomplished in 5 days through induction of an epithelial-to-mesenchymal transition. Using this model, we conducted in vivo drug screening and identified three hit drugs. One of them, adrenosterone, an inhibitor for hydroxysteroid (11-beta) dehydrogenase 1 (HSD11β1), has a suppressor effect on cell dissemination in this model. Pharmacologic and genetic inhibition of HSD11β1 suppressed metastatic dissemination of highly metastatic human cell lines in a zebrafish xenotransplantation model. Through downregulation of Snail and Slug, adrenosterone-treated cells recovered expression of E-cadherin and other epithelial markers and lost partial expression of mesenchymal markers compared with vehicle-treated cells. Taken together, our model offers a useful platform for the discovery of antimetastasis drugs targeting metastatic dissemination of cancer cells. Implications: This study describes a transgenic zebrafish model for liver tumor metastasis and it has been successfully used for identification of some drugs to inhibit metastatic dissemination of human cancer cells.
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