Pre-BCR and STAT5 Signaling in Acute Lymphoblastic Leukemia

描述(申请人提供)：前B细胞的转化导致前B细胞-急性淋巴细胞白血病(B-ALL)的发展。在儿童中，ALL(大多数是B-ALL)是最常见的肿瘤形式。因此，尽管儿童B-ALL的治疗非常有效(约80%的存活率)，但20%的无反应者仍然代表着相当大数量的儿童死于这种疾病。此外，某些类型的ALL的预后要差得多。最后，虽然ALL在成人中不太常见，但其结果要糟糕得多(约40%的存活率)。B-ALL的一个子集的特征是参与BCR前信号转导的基因存在缺陷，例如适配器蛋白BLNK。为了探索Pre-BCR信号在ALL中的作用，我们将表达固有活性的STAT5b转基因(STAT5b-CA)的小鼠与blnk+/-、btk-/-、pkc2-/-或nf：B1-/-小鼠杂交。STAT5b-CA小鼠的外显率都很低(~1-2)，而blnk+/-、Btk-/-、pkc2-/-和nf：B1-/-小鼠与WT小鼠相比没有发生白血病的报道。相反，50-100%的STAT5b-CA x blnk+/-、STAT5b-CA x Btk-/-、STAT5b-CA x pkc2-/-和STAT5b-CA x nf：B1-/-小鼠在出生后300天内均发育出B细胞。基于这些初步发现，我们假设导致STAT5激活的信号，加上BCR前信号的缺陷，共同启动ALL。我们的结果提示，STAT5和缺陷的Pre-BCR信号分别作为协同癌基因和肿瘤抑制通路，共同启动ALL。此外，我们的初步数据表明，STAT5和NFkB信号通路在未转化的Pre-B细胞中起着相互拮抗的作用，这种拮抗反馈环的扰动在启动Pre-B ALL中起着重要作用。我们将通过(I)确定STAT5参与前B细胞转化的分子机制，以及(Ii)确定STAT5和NFkB信号通路之间的拮抗如何阻止转化来检验这一假设。我们最近观察到，(I)~35%的人类ALL患者STAT5激活水平升高，(Ii)治疗前STAT5激活水平升高的患者比STAT5激活水平较低的患者预后差得多。总之，这些研究应该为STAT5的激活以及BCR前信号转导缺陷促进B-ALL前体细胞的发展提供新的分子机制；这些信息应该会在未来导致对B-ALL的更理想的治疗。

DESCRIPTION (provided by applicant): Transformation of pre B cells results in the development of pre-B cell-Acute Lymphoblastic Leukemia (B-ALL). In children, ALL (most of which are B-ALL) are the most common form of neoplasia. Thus, while treatment for pediatric B-ALL is highly effective (~80% survival), the 20% non-responders still represent a sizeable number of children that succumb to this disease. In addition, some types of ALL have a much poorer prognosis. Finally, while ALL is less common in adults, their outcome is much worse (~40% survival). A subset of B-ALL has been characterized by defects in genes involved in pre-BCR signaling, such as the adaptor protein Blnk. To explore the role of pre-BCR signaling in ALL, we crossed mice expressing a constitutively active STAT5b transgene (STAT5b-CA) to blnk+/-, btk-/-, pkc2-/-, or nf:b1-/- mice. STAT5b-CA mice develop ALL with very low penetrance (~1-2), while blnk+/-, btk-/-, pkc2-/-, and nf:b1-/- mice have not been reported to develop leukemia with increased frequency relative to WT mice. In contrast, 50-100% of STAT5b-CA x blnk+/-, STAT5b-CA x btk-/-,STAT5b-CA x pkc2-/-, and STAT5b-CA x nf:b1-/- mice developed B cell ALL within 300 days of birth. Based on these preliminary findings we hypothesize that signals leading to STAT5 activation, coupled with defects in pre-BCR signaling, cooperate to initiate ALL. Our results suggest a novel pairing of STAT5, and defective pre-BCR signaling, as cooperative oncogene and tumor suppressor pathway, respectively, that initiate ALL. In addition, our preliminary data indicate that STAT5 and NFkB signaling pathways play mutually antagonistic roles in non-transformed pre-B cells and that perturbation of this antagonistic feedback loop plays an important role in initiating pre-B ALL. We will test this hypothesis by (i) identifying the molecular mechanisms by which STAT5 entrains pre-B cell transformation, and (ii) determining how antagonism between STAT5 and NFkB signaling pathways prevents transformation. The significance of these proposed studies is underscored by our recent observations that (i) ~35% of human patients with ALL have increased levels of STAT5 activation, and (ii) patients with elevated levels of STAT5 activation prior to treatment have much poorer outcomes than those with lower levels of STAT5 activation. In summary, these studies should provide new insights into the molecular mechanisms by which activation of STAT5, coupled with defects pre-BCR signaling promotes the development of progenitor B-ALL; such information should result in more optimal therapies for B-ALL in the future.