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: 7739916
• 负责人: RICHARD J FORD
• 金额: $ 16.94万
• 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 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7739916
• 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）：地幔细胞淋巴瘤（MCL）是最耐治疗的； B细胞，非霍奇金的淋巴瘤（NHL-B），目前缺乏适当的治疗，并且在美国发病率正在增加。缺乏有效的动物模型，了解了MCL和实验疗法的病原体生理学和实验疗法，这受到了阻碍。我们最近构建了第一个经过模拟最耐治疗形式的MCL的转基因MCL模型，即Blastoid变体（MCL-BV）。该模型不仅为MCL-BV的发病机理提供了潜在的见解，而且具有分层肿瘤细胞组织，具有小但独特的肿瘤细胞亚群，具有类似于肿瘤引发细胞（TIC）的自我更新能力。我们的MCL-BV模型中的TIC种群还显示出与癌症干细胞（CSC）的相似性，该模型中可能代表了MCL-BV模型中的“原始细胞”，该模型应允许在有效的鼠MCL模型中测试癌症干细胞假设的各种预测。我们的MCL-BV模型是一种鼠双转基因（DTG），是通过越过IL14 x C-MYC单TG小鼠构建的。 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B淋巴细胞谱系中，它可能充当癌基因，除生长刺激外，还显示出重要的B细胞功能特征。 DTG小鼠随机地在3-4个月（100％的渗透率）中形成了类似于侵略性MCL-BV的NHL-B，从而使鼠B淋巴样细胞中分子和基因型变化的顺序且定义的病原体表征从出生到淋巴瘤发育。 DTG MCL-BV模型为MCL提供了多种有趣的潜在见解，但是我们在R21提案中的研究将通过识别和表征DTG/MCL-BV模型中可能的“原始单元”来理解MCL-BV个体发育中的一个方面。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。在此提案中，我们将主要关注：（1）表征DTG肿瘤细胞群体的层次结构性质，对SP种群的鉴定，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）特征的肿瘤启动细胞（TIC）； （2）进一步表征和验证我们的DTG/MCL-BV模型模拟了异常的细胞周期和组成型生长/存活信号通路激活，这是人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与CSC相关的特性，从而有助于DTG淋巴瘤的起始，肿瘤维持以及可能复发。我们还将检查众所周知的人类MCL特征，涉及Cyclind1过表达异常的细胞周期调节，以及NF-？B和PAKT的生长和生存（抗凋亡）信号通路的本构激活是否在DTG/TIC TUMOR细胞中尤其是在dtg Tumor sub-spercation中被激活的，并且可能会在dtg tumor sub-spercation中激活。 MCL-BV。公共卫生相关性：地幔细胞淋巴瘤（MCL）是最困难的B细胞非霍奇金淋巴瘤，可在临床上治疗，生存率最差。为什么MCL在临床上如此侵略性尚不清楚，而由于缺乏合适的动物模型，也阻碍了更有效的疗法的发展。我们已经开发了MCL（MCL-BV）类囊体变体的基因工程模型（双转基因； DTG），该模型将为MCL的起源/原因提供两种线索，以及一个测试新MCL药物的模型，这将在此赠款建议中开发。