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 pre-B cell receptor triggers expansion and differentiation of pre-B cells (the pre-B cell transition), as well as inhibition of V(H) to DJ(H) recombination (allelic exclusion). The latter also accounts for counter-selection of pro-B cells expressing Dmu protein (Dmu selection). However, the signaling pathways responsible for these events remain poorly defined. Here we show complete arrest of B cell development at the pre-B cell transition in BASH/CD19 double mutant mice, indicating partial redundancy of the two B cell-specific adaptors. Allelic exclusion remained intact in the double mutant mice, whereas Dmu selection was abolished in BASH mutant mice. Thus, distinct signals are required for these events. In addition, both mutant mice succumbed to pre-B cell leukemia, indicating that BASH and CD19 contribute to tumor suppression.
Ag receptor stimulation of preactivated T cells causes rapid cell death in an IL-2– and Fas-dependent manner. This phenomenon, known as activation-induced cell death (AICD), plays a pivotal role in the removal of Ag-reactive T cells after initial expansion. In this study, we report a novel form of T cell apoptosis that is distinct from classic AICD. When peripheral T cells were activated with anti-CD3 and anti-CD28 Abs precoated onto plastic plates, CD4+CD25− and CD8 T cells initially expanded but underwent massive apoptosis after 4 d. Unlike classic AICD, this type of T cell apoptosis pathway requires engagement of CD28 and expression of p53, a tumor-suppressor gene. The most striking feature of this form of apoptosis was regulatory T cell resistance. Under the same stimulating conditions, CD4+CD25+ T cells grew continuously beyond 4 d. Consequently, when the entire CD4 population was cultured with plate-bound anti-CD3 plus anti-CD28 Ab, CD4+CD25+FoxP3+ regulatory T cells outgrew non-regulatory T cells and expanded >7000-fold after 11 d. The data presented herein demonstrate a novel process of Ag-induced T cell death by sustained TCR and CD28 engagement and represent a simple and efficient procedure for the expansion of regulatory T cells in vitro.
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