Novel Pathways for Bcr-Abl transformation

Bcr-Abl 转化的新途径

• 批准号: 8701016
• 负责人: IAN P WHITEHEAD
• 金额: $ 6.67万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-03 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8701016
• 关键词: Novel; Pathways; Bcr; Abl; transformation

DESCRIPTION (provided by applicant): Numerous animal studies have demonstrated that the fusion protein p210 Bcr-Abl is the causative agent of Chronic Myelogenous Leukemia (CML), and pharmacological inhibitors (such as imatinib) that target this molecule produce effective, durable responses in many patients. Imatinib targets a tyrosine kinase activity contained within the Abl sequences that is considered to be the principle driving force behind CML. Although the success of imatinib has validated rational drug design in cancer therapy, two clinical issues are emerging in the treatment of CML. First, patients are developing resistance to imatinib by acquiring mutations within the kinase domain (acquired resistance). Second, and probably more problematic, over 95% of patients still have p210 Bcr-Abl positive cells, even after 12 months of imatinib treatment (minimal residual disease). Whether or not acquired resistance and minimal residual disease are mechanistically related is unclear, but both problems highlight the need to develop complementary inhibitors, with different modalities, that can target additional functions of p210 Bcr-Abl. Although the tumorigenic properties of p210 Bcr-Abl can be primarily attributed to the Abl-encoded kinase activity, numerous studies have determined that there are also domains present within the Bcr sequences that are required to support oncogenic activity. Although poorly characterized, these domains are intriguing since they represent unexploited targets for pharmacological intervention. In the previous funding period, our laboratory as been exploring the hypothesis that the characterization of Bcr- encoded activities will identify viable new targets for p210 Bcr-Abl inhibition. Three such activities have now been identified. First, it has been determined that the RhoGEF domain, which is autoinhibited in Bcr, is constitutively activated in p210 Bcr-Abl. Mutations that eliminate this activity in p210 Bcr-Abl exhibit diminished transforming activity in cell- and animal-based models suggesting that this domain may be required for CML. Second, it has been determined that Bcr is a regulatory component of the endosomal sorting pathway, and that this pathway is disrupted by overexpression of p210 Bcr-Abl in hematopoietic cells. This represents a novel, and completely unexplored aspect of p210 Bcr-Abl biology, which undoubtedly will be relevant to CML. Finally, it has been determined that Bcr has a nuclear function through which it can regulate levels of protein expression. This includes the c-Myc oncoprotein which is known to contribute to CML. Bcr-Abl regulates c- Myc through binding to XPB, and disruption of this interaction is also associated with diminished transforming activity in cell- and animal-based models. In this continuation application these activities will be characterized in the context of hematopoietic cells, and it will be determined whether they are viable targets for p210 Bcr-Abl inhibition. For this analysis, p210 Bcr-Abl mutants have been generated that are impaired in these activities, and which can be evaluated in cell- and animal-based models for CML. PUBLIC HEALTH RELEVANCE: Imatinib is a pharmacological inhibitor that causes clinical remission in many patients with Chronic Myelogenous Leukemia. However, imatinib controls rather than cures the disease, and many patients develop resistance to the treatment. Thus, the focus of this proposal is the development of novel approaches and inhibitors that can be used to complement imatinib treatment.

描述（由申请人提供）：许多动物研究已经证明融合蛋白p210 Bcr-Abl是慢性髓性白血病（CML）的病原体，靶向该分子的药理学抑制剂（如伊马替尼）在许多患者中产生有效、持久的反应。伊马替尼靶向Abl序列中包含的酪氨酸激酶活性，该活性被认为是CML背后的主要驱动力。尽管伊马替尼的成功验证了癌症治疗中的合理药物设计，但在CML治疗中出现了两个临床问题。首先，患者通过在激酶结构域内获得突变而对伊马替尼产生耐药性（获得性耐药）。其次，可能更有问题的是，超过95%的患者仍然有p210 Bcr-Abl阳性细胞，即使在伊马替尼治疗12个月后（微小残留病）。获得性耐药和微小残留病是否在机制上相关尚不清楚，但这两个问题都突出了开发互补抑制剂的需要，其具有不同的形式，可以靶向p210 Bcr-Abl的额外功能。许多研究已经确定在Bcr序列中也存在支持致癌活性所需的结构域。尽管这些领域的特征很差，但它们很有趣，因为它们代表了尚未开发的药物干预靶点。在上一个资助期，我们的实验室一直在探索Bcr编码活性的表征将确定p210 Bcr-Abl抑制的可行新靶点的假设。现已确定了三项此类活动。首先，已经确定在Bcr中被自身抑制的RhoGEF结构域在p210 Bcr-Abl中被组成性激活，在细胞和动物模型中，消除p210 Bcr-Abl中这种活性的突变表现出转化活性的降低，这表明该结构域可能是CML所必需的。第二，已经确定Bcr是内体分选途径的调节组分，并且该途径被造血细胞中p210 Bcr-Abl的过表达破坏。这代表了p210 Bcr-Abl生物学的一个新的、完全未探索的方面，这无疑与CML有关。最后，已经确定Bcr具有核功能，通过该核功能它可以调节蛋白质表达水平。这包括已知导致CML的c-Myc癌蛋白。Bcr-Abl通过与XPB结合来调节c-Myc，这种相互作用的破坏也与细胞和动物模型中转化活性的降低有关。在本继续申请中，这些活性将在造血细胞的背景下表征，并且将确定它们是否是p210 Bcr-Abl抑制的可行靶标。对于该分析，已经产生了这些活性受损的p210 Bcr-Abl突变体，并且可以在基于细胞和动物的CML模型中进行评估。公共卫生相关性：伊马替尼是一种药理学抑制剂，可导致许多慢性粒细胞白血病患者临床缓解。然而，伊马替尼控制而不是治愈疾病，许多患者对治疗产生耐药性。因此，该提案的重点是开发可用于补充伊马替尼治疗的新方法和抑制剂。

项目成果

Regulation of breast cancer cell motility by T-cell lymphoma invasion and metastasis-inducing protein.

• DOI: 10.1186/bcr2637
• 发表时间: 2010
• 期刊: Breast cancer research : BCR
• 作者: Adams HC 3rd;Chen R;Liu Z;Whitehead IP
• 通讯作者: Whitehead IP

Regulation of vesicle transport and cell motility by Golgi-localized Dbs.

• DOI: 10.4161/sgtp.28570
• 发表时间: 2014-01-01
• 期刊: Small GTPases
• 作者: Fitzpatrick, Ethan R;Hu, Tinghui;Whitehead, Ian P
• 通讯作者: Whitehead, Ian P

The Sec14 homology domain regulates the cellular distribution and transforming activity of the Rho-specific guanine nucleotide exchange factor Dbs.

Sec14 同源结构域调节 Rho 特异性鸟嘌呤核苷酸交换因子 Dbs 的细胞分布和转化活性。

• DOI: 10.1074/jbc.m411139200
• 发表时间: 2005
• 期刊: The Journal of biological chemistry
• 作者: Kostenko,ElenaV;Mahon,GwendolynM;Cheng,Li;Whitehead,IanP
• 通讯作者: Whitehead,IanP

Ubiquitin-mediated interaction of p210 BCR/ABL with β-catenin supports disease progression in a murine model for chronic myelogenous leukemia.

泛素介导的 p210 BCR/ABL 与 β-连环蛋白的相互作用支持慢性粒细胞白血病小鼠模型中的疾病进展。

• DOI: 10.1182/blood-2013-01-481184
• 发表时间: 2013
• 期刊: Blood
• 影响因子: 20.3
• 作者: Chen,Ru;Hu,Tinghui;Mahon,GwendolynM;Tala,Ilona;Pannucci,NicoleL;Ozer,HarveyL;Whitehead,IanP
• 通讯作者: Whitehead,IanP