BLNK suppresses pre-B-cell leukemogenesis through inhibition of JAK3
BLNK suppresses pre-B-cell leukemogenesis through inhibition of JAK3
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DOI：
10.1182/blood-2008-07-166355
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发表时间：
2009-02-12
期刊：
影响因子：
20.3
通讯作者：
Kitamura, Daisuke
中科院分区：
文献类型：
--
作者：
Nakayama, Joji;Yamamoto, Mutsumi;Kitamura, Daisuke
前B细胞白血病在BLNK缺陷小鼠中自发发生，儿童中的前B细胞急性淋巴细胞白血病细胞通常缺乏BLNK蛋白表达，表明BLNK具有肿瘤抑制剂的功能。然而，BLNK抑制前B细胞白血病的机制，以及与BLNK缺陷合作导致白血病发生的其他遗传改变的鉴定，仍然是未知的。在这里，我们证明了JAK 3/STAT 5信号通路在来自BLNK-/-小鼠的前B白血病细胞中被组成性激活，主要是由于IL-7的自分泌产生。抑制IL-7 R信号或JAK 3/STAT 5活性导致诱导p27（kip 1）表达和细胞周期阻滞，伴随白血病细胞凋亡。转基因来源的组成型活性STAT 5（STAT 5 b-CA）与BLNK的缺失强烈协同以在体内引发白血病。在白血病细胞中，外源表达的BLNK抑制自分泌JAK 3/STAT 5信号传导，导致p27（kip 1）诱导，细胞周期停滞和凋亡。BLNK对JAK 3的抑制依赖于BLNK与JAK 3的结合。这些数据表明，BLNK通常通过直接抑制JAK 3来调节前B细胞的IL-7依赖性增殖和存活。因此，BLNK的体细胞丢失和导致Jak/STAT 5途径的组成性激活的伴随突变导致前B细胞白血病的产生。（血。2009; 113：1483-1492）
Pre-B-cell leukemia spontaneously develops in BLNK-deficient mice, and pre-B-cell 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 in pre-B leukemia cells derived from BLNK-/- mice, mostly due to autocrine production of IL-7. Inhibition of IL-7R signaling or JAK3/STAT5 activity resulted in the induction of p27(kip1) expression and cell-cycle arrest, accompanied by apoptosis in the leukemia cells. Transgene-derived constitutively active STAT5 (STAT5b-CA) strongly synergized with the loss of BLNK to initiate leukemia in vivo. In the leukemia cells, exogenously expressed BLNK inhibited autocrine JAK3/STAT5 signaling, resulting in p27(kip1) induction, cell-cycle arrest, and apoptosis. BLNK-inhibition of JAK3 was dependent on the binding of BLNK to JAK3. These data indicate that BLNK normally regulates IL-7-dependent proliferation and survival of pre-B cells through direct inhibition of JAK3. Thus, somatic loss of BLNK and concomitant mutations leading to constitutive activation of Jak/STAT5 pathway result in the generation of pre-B-cell leukemia. ( Blood. 2009; 113: 1483-1492)