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（由申请方提供）：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，在美国的发病率正在增加。了解MCL的病理生理学和用于更好的MCL治疗的实验疗法由于缺乏有效的动物模型而受到阻碍。我们最近构建了第一个转基因MCL模型，该模型密切模拟了MCL的最耐药形式，即胚状体变体（MCL-BV）。该模型不仅为MCL-BV的发病机制提供了潜在的见解，而且还具有分级肿瘤细胞组织，具有小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群体还显示出与癌症干细胞（CSC）的相似性，其可以代表该MCL-BV模型中的“起源细胞”，这应该允许在有效的鼠MCL模型中测试癌症干细胞假设的各种预测。我们的MCL-BV模型是通过将IL 14 x c-myc单TG小鼠杂交而构建的鼠双转基因（DTG）。IL-14是正常B淋巴细胞的细胞因子生长因子，在NHL-B中过表达，在NHL-B中它可以作为B淋巴细胞谱系中的癌基因发挥作用，显示出除了生长刺激之外的重要B细胞功能特征。DTG小鼠在3-4个月时（100%复发率）随机发生类似于侵袭性MCL-BV的NHL-B，从而允许从出生到淋巴瘤发生，在实验上对小鼠B淋巴细胞区室中的分子和基因型改变进行连续和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提案中的研究将集中于通过识别和表征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）小鼠中的可移植性。在本研究中，我们将主要关注：（1）描述DTG肿瘤细胞群的分级性质，鉴定SP群以支持我们的MCL模型显示具有癌症干细胞（CSC）特征的肿瘤起始细胞（TIC）的假设;（2）进一步表征和验证我们的DTG/MCL-BV模型模拟了异常细胞周期和组成性生长。存活信号传导途径活化，人MCL-BV的特征。我们的研究将探讨在DTG/MCL-BV模型中推定的MCL/ TIC的CSC相关性质如何有助于DTG淋巴瘤的起始、肿瘤维持和可能的复发。我们还将研究是否众所周知的人类MCL的特点，涉及异常的细胞周期调控与cyclinD 1过表达，和NF-？B和pAKT生长和存活（抗凋亡）信号传导途径也在DTG/TIC肿瘤细胞和/或其他DTG肿瘤亚群中被激活，这可能是在MCL患者，特别是MCL-BV患者中观察到的临床治疗抗性的原因。公共卫生相关性：套细胞淋巴瘤（MCL）是临床上治疗最困难的B细胞非霍奇金淋巴瘤，预后最差。为什么MCL在临床上如此具有侵袭性尚不清楚，这沿着缺乏合适的动物模型阻碍了更有效疗法的开发。我们已经开发了MCL（MCL-BV）的胚状体变体的基因工程模型（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