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...
Interaction of the TCR complex with self- or foreign peptides is a central event in the immune responses. Upon TCR stimulation, a protein-tyrosine kinase (PTK), ZAP-70, is recruited to signaling units of the TCR complex, such as TCRzeta, to play an essential role in T cell activation. Here, we find that mice lacking adaptor proteins Dok-1 and Dok-2 show augmented responses to thymus-dependent, but not thymus-independent, antigens, and that their T cells show elevated responses to TCR stimulation, including the activation of ZAP-70 and subsequent proliferation and cytokine production. Furthermore, the forced expression of Dok-1 or Dok-2 in a CD3(+)CD4(+) T cell clone inhibited the activation of ZAP-70 upon TCR stimulation. Interestingly, the Dok-1 and Dok-2 COOH-terminal moieties bearing the src homology 2 target motifs were dispensable for this negative regulation, even though they are crucial for the known adaptor function of Dok-family proteins. Thus, by an as yet unidentified mechanism, Dok-1 and Dok-2 play an essential role in the negative regulation of TCR signaling. Consistently, all mice lacking these proteins exhibited elevated titers of antibodies to double-stranded DNA and developed lupus-like renal disease.
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