Murine Models for Mantle Cell Lymphoma: The role of tumor initiating cells (TIC)

套细胞淋巴瘤小鼠模型：肿瘤起始细胞 (TIC) 的作用

• 批准号: 7847668
• 负责人: RICHARD J FORD
• 金额: $ 20.33万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7847668
• 关键词: Abnormal Cell; Accounting; Animal Model; Apoptotic; Applications Grants; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; Birth; Cell Cycle; Cell Cycle Regulation; Cell Line; Cells; Characteristics; Clinical; Complex; Cytogenetics; Development; Developmental Therapeutics Program; Engineering; Functional disorder; Future; Gene Expression; Genes; Genetic; Growth; Growth Factor; Human; Human Characteristics; IL14 gene; Immune; Immunophenotyping; Incidence; Leukemic Cell; Lymphocyte; Lymphoid Cell; Lymphoma; Maintenance; Mantle Cell Lymphoma; Modeling; Molecular; Molecular Genetics; Mus; Nature; Oncogenes; Oncogenic; Pathogenesis; Patients; Penetrance; Pharmaceutical Preparations; Physiological; Physiological Processes; Physiology; Population; Process; Property; Prospective Studies; Recurrence; Resistance; Role; Side; Signal Pathway; Simulate; Stem cells; Testing; Therapeutic; Therapeutic Agents; Transgenic Mice; Transgenic Organisms; Transplantation; Tumor-Derived; Variant; c-myc Genes; cancer stem cell; cell growth; clinically significant; cytokine; effective therapy; insight; interest; mRNA Differential Displays; neoplastic cell; outcome forecast; precursor cell; public health relevance; research study; selective expression; self-renewal; therapy resistant; tumor; tumor growth; tumor initiation

DESCRIPTION (provided by applicant): Mantle cell lymphoma (MCL) is the most therapy-resistant; B cell, non-Hodgkin's lymphoma (NHL-B) that currently lacks adequate therapy, and is increasing in incidence in the USA. Understanding the patho- physiology of MCL and experimental therapeutics for better MCL therapy has been hampered by the lack of a valid animal model. We have recently constructed the first transgenic MCL model that closely simulates the most therapy-resistant form of MCL, the Blastoid variant (MCL-BV). This model not only provides potential insights into the pathogenesis of MCL-BV, but also has a hierarchical tumor cell organization, with a small but distinct tumor cell subpopulation with self-renewal capabilities that resemble tumor initiating cells (TIC). The TIC population in our MCL-BV model also shows similarities to Cancer Stem Cells (CSC) that may represent the "cell of origin" in this MCL-BV model that should allow for testing various predictions of the Cancer Stem cell hypothesis, in a valid murine MCL model. Our MCL-BV model is a murine double transgenic (DTG) that was constructed by crossing IL14 x c-myc single TG mice. IL-14, a cytokine growth factor for normal B-lymphocytes, is over-expressed in NHL-B, where it may function as an oncogene in the B lymphocytic lineage, showing important B cell functional characteristics in addition to growth stimulation. DTG mice stochastically develop NHL-B resembling aggressive MCL-BV by 3-4 months (100% penetrance), allowing for sequential and defined patho-physiologic characterization of molecular and genotypic alterations in the murine B lymphoid cell compartment experimentally, from birth to lymphoma development. The DTG MCL-BV model provides multiple interesting potential insights into MCL, but our studies in this R21 proposal will focus on understanding one aspect in MCL-BV ontogeny, by identifying and characterizing a possible "cell of origin" in DTG/MCL-BV model. These CSC characteristics include tumor cell "self-renewal" characteristics and transplantabilty into immune-deficient (SCID) mice. In this proposal, we will focus primarily on: (1) characterizing the hierarchical nature of DTG tumor cell populations, identification of SP populations to support our hypothesis that our MCL model displays Tumor Initiating Cells (TIC) with Cancer Stem Cell (CSC) characteristics; and (2) further characterizing and validating that our DTG/MCL-BV model simulates anomalous cell cycle and constitutive growth/survival signaling pathway activation, characteristic of human MCL-BV. Our studies will explore how CSC-associated properties of putative MCL/ TIC in the DTG/MCL-BV model, contributes to the initiation, tumor maintenance, and possibly recurrence of the DTG lymphoma. We will also examine whether well-known human MCL characteristics, involving abnormal cell cycle regulation with cyclinD1 over-expression, and the constitutive activation of the NF-?B and pAKT growth and survival (anti-apoptotic) signaling pathways, are also activated in DTG/TIC tumor cells and/or other DTG tumor sub- populations, that may account for the clinical therapeutic resistance seen in patients with MCL, and particularly MCL-BV. PUBLIC HEALTH RELEVANCE: Mantle cell lymphoma (MCL) is the most difficult B cell Non-Hodgkin lymphoma to treat clinically, with the worst survival prognosis. Why MCL is so clinically aggressive is not known, which along with the lack of a suitable animal model has hampered development of more effective therapies. We have developed a genetically engineered model (double transgenic; DTG) of the blastoid variant of MCL (MCL-BV) that will provide both clues to the origin/causes of MCL as well as a model to test new MCL drugs, which will be developed in this grant proposal.

描述（由申请人提供）：套细胞淋巴瘤（MCL）是最难治疗的； B 细胞非霍奇金淋巴瘤 (NHL-B) 目前缺乏足够的治疗方法，并且在美国的发病率正在增加。由于缺乏有效的动物模型，了解 MCL 的病理生理学和更好的 MCL 治疗的实验疗法受到了阻碍。我们最近构建了第一个转基因 MCL 模型，该模型密切模拟了最难治疗的 MCL 形式，即 Blastoid 变体 (MCL-BV)。该模型不仅为 MCL-BV 的发病机制提供了潜在的见解，而且还具有分层的肿瘤细胞组织，其中有少量但独特的肿瘤细胞亚群，具有类似于肿瘤起始细胞 (TIC) 的自我更新能力。我们的 MCL-BV 模型中的 TIC 群体也显示出与癌症干细胞 (CSC) 的相似性，CSC 可能代表此 MCL-BV 模型中的“起源细胞”，这应该允许在有效的小鼠 MCL 模型中测试癌症干细胞假设的各种预测。我们的 MCL-BV 模型是通过 IL14 x c-myc 单 TG 小鼠杂交构建的鼠双转基因 (DTG) 模型。 IL-14 是正常 B 淋巴细胞的细胞因子生长因子，在 NHL-B 中过度表达，它可能作为 B 淋巴细胞谱系中的癌基因发挥作用，除了生长刺激外，还显示出重要的 B 细胞功能特征。 DTG 小鼠在 3-4 个月内随机发展出类似于侵袭性 MCL-BV 的 NHL-B（外显率 100%），从而可以通过实验对小鼠 B 淋巴细胞区室中从出生到淋巴瘤发展的分子和基因型变化进行连续且明确的病理生理学表征。 DTG MCL-BV 模型为 MCL 提供了多种有趣的潜在见解，但我们在 R21 提案中的研究将侧重于通过识别和表征 DTG/MCL-BV 模型中可能的“起源细胞”来了解 MCL-BV 个体发育的一个方面。这些 CSC 特征包括肿瘤细胞“自我更新”特征和移植到免疫缺陷 (SCID) 小鼠中的能力。在本提案中，我们将主要关注：（1）表征DTG肿瘤细胞群的层次性质，识别SP群以支持我们的假设，即我们的MCL模型显示具有癌症干细胞（CSC）特征的肿瘤起始细胞（TIC）； (2) 进一步表征和验证我们的 DTG/MCL-BV 模型模拟异常细胞周期和组成性生长/生存信号通路激活，这是人类 MCL-BV 的特征。我们的研究将探讨 DTG/MCL-BV 模型中假定的 MCL/TIC 的 CSC 相关特性如何有助于 DTG 淋巴瘤的发生、肿瘤维持和可能的复发。我们还将检查众所周知的人类 MCL 特征，包括 cyclinD1 过表达的异常细胞周期调节，以及 NF-κB 和 pAKT 生长和存活（抗凋亡）信号通路的组成型激活，是否也在 DTG/TIC 肿瘤细胞和/或其他 DTG 肿瘤亚群中被激活，这可能解释了 MCL 患者的临床治疗耐药性，特别是 MCL-BV。公共卫生相关性：套细胞淋巴瘤 (MCL) 是临床上最难治疗的 B 细胞非霍奇金淋巴瘤，生存预后最差。为什么 MCL 在临床上如此具有侵袭性尚不清楚，加上缺乏合适的动物模型，阻碍了更有效疗法的开发。我们开发了 MCL 母细胞变体 (MCL-BV) 的基因工程模型（双转基因；DTG），该模型将提供 MCL 起源/原因的线索，以及测试新 MCL 药物的模型，该模型将在本拨款提案中开发。

项目成果

Side population of a murine mantle cell lymphoma model contains tumour-initiating cells responsible for lymphoma maintenance and dissemination.

鼠地幔细胞淋巴瘤模型的侧种群包含负责淋巴瘤维持和传播的肿瘤发射细胞。

• DOI: 10.1111/j.1582-4934.2009.00865.x
• 发表时间: 2010-06
• 期刊: Journal of cellular and molecular medicine
• 影响因子: 5.3
• 作者: Vega F;Davuluri Y;Cho-Vega JH;Singh RR;Ma S;Wang RY;Multani AS;Drakos E;Pham LV;Lee YC;Shen L;Ambrus J Jr;Medeiros LJ;Ford RJ
• 通讯作者: Ford RJ