(PQ1) Genomic characterization of mesenchymal stromal cells in Monoclonal Gammopathy of Undermined Significance (MGUS)

(PQ1) 意义被削弱的单克隆丙种球蛋白病 (MGUS) 中间充质基质细胞的基因组特征

• 批准号: 9917699
• 负责人: Irene M. Ghobrial
• 金额: $ 43.85万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9917699
• 关键词: 1p13; Affect; Age-Years; Anemia; Applications Grants; Bone Marrow; CRISPR/Cas technology; Cell Aging; Cells; Chromosomal translocation; Chromosome abnormality; Clonal Evolution; Clonal Expansion; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Copy Number Polymorphism; DNA Sequence Alteration; Development; Diagnostic; Disease; Disease Progression; Distant; Event; Future; Gene Expression; Genes; Genetic; Genomics; Grant; Hypercalcemia; Image; Immunoglobulin A; Immunoglobulin G; In Vitro; KRAS2 gene; Kidney Failure; Lead; Lesion; Malignant - descriptor; Malignant Neoplasms; Mass Spectrum Analysis; Modeling; Molecular Abnormality; Monoclonal Gammapathies; Monoclonal gammopathy of uncertain significance; Multiple Myeloma; Mus; Mutation; NRAS gene; Participant; Patients; Plasma Cells; Point Mutation; Population; Proliferating; Property; Proteins; Regulation; Risk; Risk Reduction; Role; Sampling; Serum; Site; Somatic Mutation; Stromal Cells; Symptoms; Testing; Therapeutic Agents; Therapeutic Intervention; Therapeutic Uses; Tissues; Validation; base; bone; cancer cell; cell type; chromosome loss; design; epigenomics; in vivo; in vivo Model; knockout gene; mesenchymal stromal cell; mouse model; multiple myeloma M Protein; novel; premalignant; prevent; public health relevance; research study; stem cells; transcriptomics; tumor; tumor initiation; tumor progression; tumorigenesis; virtual

 DESCRIPTION (provided by applicant): Monoclonal gammopathy of undetermined significance (MGUS) is one of the most common pre-malignant disorders and affects approximately 3.5% of the population over 50 years of age. This grant application aims to test the provocative question PQ1. For tumors that arise from a pre-malignant field, what properties of cells in this field can be used to design strategies to inhibit the development of future tumors Recent studies showed that tumors are more than insular masses of proliferating cancer cells. Instead, they are complex tissues composed of multiple distinct cell types that participate in heterotypic interactions with one another. Here, we hypothesize that normal bone marrow mesenchymal stromal cells (MSCs) adjacent to the early premalignant MGUS cells are active participants in tumorigenesis and clonal evolution rather than passive bystanders; as such, these cells contribute to the development of multiple myeloma (MM). We will test this hypothesis in 3 specific Aims. In Specific Aim 1, we will elucidate genomic/transcriptomic events that govern alterations in MSCs at the premalignant stage of MGUS. We will perform integrative characterization of genomic, epigenomic and transcriptomic changes that occur in MSCs present near MGUS cells in bulk and at the single cell level. Further validation of specific target will be performed at the protein level to identify the spatial localization of these altered MSCs i the bone marrow niche using CyTOF mass spectrometry imaging. In Specific Aim 2, we will identify the sequential acquisition of genomic lesions in MSCs in the early premalignant stage and during disease progression in a murine model. Here, we will define the changes that occur in MSCs during the first genetic event in the premalignant plasma cells and identify changes that occur in the proximity of clonal plasma cells at the early MGUS stages vs. those that are present in distant bone marrow sites. We will examine whether MSCs alterations precede the early genetic hit (permissive microenvironment) or are acquired after MGUS development (acquired alterations). We will also define genomic and gene expression changes that occur in MSCs with stem cell aging in these mice. In Specific Aim 3, we will validate specific targets using CRISPR-based gene knockout of highly prioritized genes based on the studies performed in Aims 1 and 2 to functionally interrogate their specific role on MSCs and their regulation of tumor progression using in vitro and in vivo models. Furthermore, we will develop MSC-specific genomic alterations using CRISPR-cas9 mice crossed with Osx-cre mice to define the role of these target genes in regulating tumor initiation and MGUS progression in murine MM models. These focused research studies will help define the contributing role of MSCs in the early stages of MGUS development and clonal progression to MM. By identifying novel targets that regulate clonal evolution at the early premalignant stage of MGUS, we may be able to develop therapeutic agents that prevent or delay progression from MGUS to overt MM. Indeed, by eradicating the disease at the precursor stages, MM may become a preventable disease.

 描述（通过应用程序提供）：不确定意义（MGU）的单克隆伽马病是最常见的恶性疾病之一，大约影响50岁以上人口的3.5％。该赠款申请旨在测试挑衅性问题PQ1。对于源自现场前场的肿瘤，该领域细胞的特性可用于设计抑制未来肿瘤发展的策略，最近的研究表明，肿瘤不仅仅是增殖癌细胞的岛状肿块。取而代之的是，它们是由多种不同的细胞类型组成的复杂组织，这些细胞类型参与了彼此的异型相互作用。在这里，我们假设正常的骨髓间充质基质细胞（MSC）与早期预先辩护的MGUS细胞相邻的是肿瘤发生和克隆进化而不是被动旁观者的活跃参与者。因此，这些细胞有助于我们在3个特定目标中检验这一假设。在特定的目标1中，我们将阐明在MGUS的临时阶段控制MSC改变的基因组/转录事件。我们将进行基因组，表观基因组学和转录组变化的综合表征，这些变化在MGUS细胞附近的大量和单细胞水平上发生。将在蛋白质水平上进行进一步验证特定靶标，以确定这些改变的MSC i的空间定位，使用质谱质谱成像骨髓生态位。在特定的目标2中，我们将在早期预临床阶段和鼠模型中的疾病进展过程中确定MSC中基因组病变的顺序获得。在这里，我们将定义在初期浆细胞中第一个遗传事件中MSC中发生的变化，并确定在早期MGUS阶段克隆等离子体细胞接近的变化，而在较早的骨髓部位中存在的变化。我们将检查MSC的改变是否先于早期遗传命中（允许微环境）还是在MGUS发育后获得（获得的变化）。我们还将定义这些小鼠干细胞衰老的MSC中发生的基因组和基因表达变化。在特定的目标3中，我们将根据AIM 1和2中的研究来验证基于CRISPR的基因敲除高优先基因的基因敲除，以便在功能上询问其在MSC上的特定作用，并使用体外和体内模型来调节其对肿瘤进展的调节。此外，我们将使用与OSX-CRE小鼠交叉的CRISPR-CAS9小鼠开发MSC特异性基因组改变，以定义这些靶基因在控制鼠MM模型中控制肿瘤倡议和MGUS进展中的作用。这些重点研究将有助于定义MSC在MGUS发育和克隆进展为MM的早期阶段的促进作用。通过识别在MGU早期预立阶段调节克隆进化的新型靶标，我们也许能够开发预防或延迟从mgus到明显MM进展的治疗剂。实际上，通过消除前体阶段的疾病，MM可能成为可预防的疾病。

项目成果

Immune biomarkers of response to immunotherapy in patients with high-risk smoldering myeloma.

• DOI: 10.1016/j.ccell.2022.10.017
• 发表时间: 2022-11-14
• 期刊: CANCER CELL
• 影响因子: 50.3
• 作者: Sklavenitis-Pistofidis, Romanos;Aranha, Michelle P.;Redd, Robert A.;Baginska, Joanna;Haradhvala, Nicholas J.;Hallisey, Margaret;Dutta, Ankit K.;Savell, Alexandra;Varmeh, Shohreh;Heilpern-Mallory, Daniel;Ujwary, Sylvia;Zavidij, Oksana;Aguet, Francois;Su, Nang K.;Lightbody, Elizabeth D.;Bustoros, Mark;Tahnri, Sabrin;Mouhieddine, Tarek H.;Wu, Ting;Flechon, Lea;Anand, Shankara;Rosenblatt, Jacalyn M.;Zonder, Jeffrey;Vredenburgh, James J.;Boruchov, Adam;Bhutani, Manisha;Usmani, Saad Z.;Matous, Jeffrey;Yee, Andrew J.;Jakubowiak, Andrzej;Laubach, Jacob;Manier, Salomon;Nadeem, Omar;Richardson, Paul;Badros, Ashraf Z.;Mateos, Maria-Victoria;Trippa, Lorenzo;Getz, Gad;Ghobrial, Irene M.
• 通讯作者: Ghobrial, Irene M.

Hydrogen Peroxide-Triggered Disassembly of Boronic Ester-Cross-Linked Brush-Arm Star Polymers.

• DOI: 10.1021/acsmacrolett.3c00323
• 发表时间: 2023-08-15
• 期刊: ACS MACRO LETTERS
• 影响因子: 7.015
• 作者: Costa, Leticia C.;Shieh, Peyton;Zafar, Hadiqa;Thiabaud, Gregory;Bobylev, Eduard O.;Jasanoff, Alan;Johnson, Jeremiah A.
• 通讯作者: Johnson, Jeremiah A.

MinimuMM-seq: Genome Sequencing of Circulating Tumor Cells for Minimally Invasive Molecular Characterization of Multiple Myeloma Pathology.

MinimuMM-seq：循环肿瘤细胞的基因组测序，用于多发性骨髓瘤病理学的微创分子表征。

• DOI: 10.1158/2159-8290.cd-22-0482
• 发表时间: 2023
• 期刊: Cancer discovery
• 影响因子: 28.2
• 作者: Dutta,AnkitK;Alberge,Jean-Baptiste;Lightbody,ElizabethD;Boehner,CodyJ;Dunford,Andrew;Sklavenitis-Pistofidis,Romanos;Mouhieddine,TarekH;Cowan,AnnieN;Su,NangKham;Horowitz,EricaM;Barr,Hadley;Hevenor,Laura;Beckwith,JennaB;Per
• 通讯作者: Per

Bortezomib overcomes the negative impact of CXCR4 mutations on survival of Waldenstrom macroglobulinemia patients.

硼替佐米克服了 CXCR4 突变对华氏巨球蛋白血症患者生存的负面影响。

• DOI: 10.1182/blood-2018-07-863241
• 发表时间: 2018
• 期刊: Blood
• 影响因子: 20.3
• 作者: Sklavenitis-Pistofidis,Romanos;Capelletti,Marzia;Liu,Chia-Jen;Reidy,Mairead;Zavidij,Oksana;Huynh,Daisy;Henrick,Patrick;Savell,Alexandra;Reyes,Kaitlen;Rivotto,Bradley;Bustoros,Mark;Perilla-Glen,Adriana;Trippa,Lorenzo;Castillo,Jor
• 通讯作者: Castillo,Jor