Defining the landscape of structural alterations in African American Multiple Myeloma

定义非裔美国人多发性骨髓瘤的结构改变

基本信息

  • 批准号:
    10651845
  • 负责人:
  • 金额:
    $ 21.51万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-07-01 至 2025-06-30
  • 项目状态:
    未结题

项目摘要

Summary Multiple Myeloma is a malignancy of long-lived plasma cells of the bone marrow and is the second most common hematologic malignancy, with over 34,000 new cases and nearly 13,000 deaths expected in the US in 2021. However, amongst African Americans, myeloma is the most common hematologic malignancy with the incidents rate between 2-3 times higher than that observed in Caucasians. Consistent with this finding, the precursor to myeloma, Monoclonal Gammopathy of Undetermined Significance (MGUS) is also observed at a higher frequency in African Americans. Thus, the increased frequency of myeloma is likely to due to underlying factors that result in both the development of MGUS as well as its progression to myeloma. Translocations that juxtapose oncogenes to the potent enhancers of the immunoglobulin heavy chain (IgH) or trisomies of odd- numbered chromosomes (hyperdiploidy) are the initiating events in nearly all myelomas. However, these are rarely sufficient to cause myeloma, which almost always have additional copy number alterations (e.g., del17p, amp1q21) and/or mutations (e.g. KRAS, TP53) observed at diagnosis and these influence outcome. Interestingly African Americans tend to have genomic alterations that would predict a superior outcome, however we have found that in patients treated identically with the current standard of care at our institution, there is no difference in the patient outcomes. Additionally, in the MMRF CoMMpass study, African Americans do worse than Caucasians despite no difference in the treatment and being diagnosed at a significantly earlier age, which is typically considered a good prognostic marker. Together these data suggest that our current approaches are either not accurately predicting risk or our therapeutic approaches are not optimized for the African American population. Our recent finding suggest that these events could be related. Utilizing whole genome sequencing that is part of the MMRF CoMMpass study, we performed an analysis of the structural landscape of newly diagnosed multiple myeloma. We found that patients that have translocations in the immunoglobulin lambda light chain locus (IgL) have a significantly worse outcome than other patients in the study. IgL translocations were found in 10% of the population and 70% were associated with hyperdiploid myeloma, a good prognostic marker routinely tested for clinically whereas IgL events are not. Thus, these patients were misdiagnosed with lower risk disease. We also demonstrated that the likely cause of misdiagnosis was resistance to one of the backbone myeloma drugs, lenalidomide. African American patients with IgL translocations experienced strikingly worse outcomes than their European American counterparts. Based on these findings we hypothesize that there are additional structural events that are not routinely tested for which can influence outcomes and that these may differ in African American myeloma. These events may also contribute to the early onset of disease. We propose two Specific Aims to test this hypothesis as well as the development of a test to detect these changes.
总结 多发性骨髓瘤是骨髓中长寿命浆细胞的恶性肿瘤, 血液恶性肿瘤,预计2021年美国将有超过34,000例新发病例和近13,000例死亡。 然而,在非洲裔美国人中,骨髓瘤是最常见的血液恶性肿瘤, 比在高加索人中观察到的高2-3倍。与这一发现相一致的是, 骨髓瘤,意义不明的单克隆丙种球蛋白病(MGUS)也在较高的 非洲裔美国人的频率。因此,骨髓瘤发生率的增加可能是由于潜在因素 导致MGUS的发展以及其向骨髓瘤的进展。的易位 将癌基因与免疫球蛋白重链(IgH)的有效增强子或奇- 编号的染色体(超二倍体)是几乎所有骨髓瘤的起始事件。不过这些都是 很少足以引起骨髓瘤,其几乎总是具有额外的拷贝数改变(例如,del17p, amp 1 q21)和/或突变(如KRAS,TP 53),这些影响结果。 然而,有趣的是,非洲裔美国人倾向于有基因组改变,这将预测一个上级的结果, 我们发现,在我们机构采用当前标准治疗的患者中, 患者结果的差异。此外,在MMRF CoMMPass研究中,非洲裔美国人的表现更差。 尽管在治疗上没有差异,而且在明显更早的年龄被诊断出来, 通常被认为是良好的预后标志物。这些数据表明,我们目前的方法是 要么不能准确预测风险,要么我们的治疗方法不适合非洲裔美国人, 人口我们最近的发现表明这些事件可能是相关的。利用全基因组测序 这是MMRF CoMMPass研究的一部分,我们对新的 诊断为多发性骨髓瘤我们发现免疫球蛋白λ发生易位的患者 轻链基因座(IgL)的患者比研究中的其他患者具有显著更差的结果。IgL易位 在10%的人群中发现,70%与超二倍体骨髓瘤相关, 标记物进行常规临床检测,而IgL事件则不进行。因此,这些患者被误诊为 低风险疾病。我们还证明了误诊的可能原因是对其中一种 骨髓瘤骨干药物来那度胺患有IgL易位的非洲裔美国人患者经历了惊人的 结果比欧洲的美国同行更糟糕。基于这些发现,我们假设, 是额外的结构性事件,这些事件没有进行常规测试,可能会影响结果, 可能与非裔美国人骨髓瘤不同。这些事件也可能导致疾病的早期发作。我们 提出了两个具体目标来检验这一假设,以及一个测试来检测这些变化的发展。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Lawrence H. Boise其他文献

Ectopic NSD2 Remodels H3K36me2 and DNA Methylation to Promote Oncogenic Gene Expression in Multiple Myeloma
  • DOI:
    10.1182/blood-2024-210929
  • 发表时间:
    2024-11-05
  • 期刊:
  • 影响因子:
  • 作者:
    Robert M Chavez;Doris R. Powell;Kiran Lakhani;John Attelah;Erin Flynt;Terry Connolly;Mark Hamilton;George Mulligan;Daniel Auclair;Jonathan Keats;Paula M Vertino;Lawrence H. Boise;Sagar Lonial;Karen N Conneely;Benjamin G. Barwick
  • 通讯作者:
    Benjamin G. Barwick
Tumor Intrinsic and Antigen-Independent Resistance Mechanisms to Bispecific T Cell Engagers in Multiple Myeloma
  • DOI:
    10.1182/blood-2024-211979
  • 发表时间:
    2024-11-05
  • 期刊:
  • 影响因子:
  • 作者:
    Holly Lee;Sungwoo Ahn;Mansour Poorebrahim;David Jung;Sacha Benaoudia;Noémie Leblay;Francesco Maura;Lawrence H. Boise;Paola Neri;Nizar J. Bahlis
  • 通讯作者:
    Nizar J. Bahlis
Targeting ABCD1-ACOX1-MET/IGF1R axis suppresses multiple myeloma
靶向 ABCD1-ACOX1-MET/IGF1R 轴抑制多发性骨髓瘤
  • DOI:
    10.1038/s41375-025-02522-9
  • 发表时间:
    2025-01-30
  • 期刊:
  • 影响因子:
    13.400
  • 作者:
    Zhannan Han;Zhibo Yan;Zhehan Ma;Yihui Wang;Maja Beus;Junqi Lu;Loren B. Weidenhammer;Kiran Lakhani;Jingyun Lee;John D. Civils;Cristina M. Furdui;Liang Liu;Jian Wu;Yubin Kang;Erhard Bieberich;Lawrence H. Boise;Mikhail A. Nikiforov
  • 通讯作者:
    Mikhail A. Nikiforov
Tumor-Immune Architecture and the Regulation of Antigen-Specific T-Cell Infiltration in Multiple Myeloma and Premalignant Plasma Cell Disorders
  • DOI:
    10.1182/blood-2022-169558
  • 发表时间:
    2022-11-15
  • 期刊:
  • 影响因子:
  • 作者:
    Hope Robinson;Nancy Villa;David L Jaye;Ajay K. Nooka;Alyssa Duffy;Samuel McCachren;Julia Manalo;Jeffrey M. Switchenko;Ava Horvat;Vaunita C Parihar;Jingjing Gong;Yan Liang;Geoffrey Smith;Vikas A Gupta;Lawrence H. Boise;Jonathan L. Kaufman;Craig C Hofmeister;Nisha Joseph;Sagar Lonial;Kavita Dhodapkar
  • 通讯作者:
    Kavita Dhodapkar
Genomic Determinants of Clinical Outcomes in Multiple Myeloma with t(11;14)(CCND1;IGH) Treated with Venetoclax
  • DOI:
    10.1182/blood-2024-204071
  • 发表时间:
    2024-11-05
  • 期刊:
  • 影响因子:
  • 作者:
    Marcella Kaddoura;J Erin Wiedmeier-Nutor;Vikas A. Gupta;Bachisio Ziccheddu;Suganti Shivaram;Hongwei Tang;Rodrigo Fonseca;Michael Durante;Shannon M Matulis;Tomas Jelinek;Ola Landgren;Constantine S Mitsiades;P. Leif Bergsagel;Esteban Braggio;Lawrence H. Boise;Rafael Fonseca;Shaji Kumar;Francesco Maura;Linda B. Baughn
  • 通讯作者:
    Linda B. Baughn

Lawrence H. Boise的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Lawrence H. Boise', 18)}}的其他基金

Defining the landscape of structural alterations in African American Multiple Myeloma
定义非裔美国人多发性骨髓瘤的结构改变
  • 批准号:
    10510606
  • 财政年份:
    2022
  • 资助金额:
    $ 21.51万
  • 项目类别:
Training Program in Biochemistry, Cell and Molecular Biology
生物化学、细胞和分子生物学培训项目
  • 批准号:
    10393719
  • 财政年份:
    2020
  • 资助金额:
    $ 21.51万
  • 项目类别:
Training Program in Biochemistry, Cell and Development Biology
生物化学、细胞和发育生物学培训项目
  • 批准号:
    10626006
  • 财政年份:
    2020
  • 资助金额:
    $ 21.51万
  • 项目类别:
Training Program in Biochemistry, Cell and Development Biology
生物化学、细胞和发育生物学培训项目
  • 批准号:
    10190967
  • 财政年份:
    2020
  • 资助金额:
    $ 21.51万
  • 项目类别:
Training Program in Biochemistry, Cell and Development Biology
生物化学、细胞和发育生物学培训项目
  • 批准号:
    10409738
  • 财政年份:
    2020
  • 资助金额:
    $ 21.51万
  • 项目类别:
The Role of CD86 in Multiple Myeloma
CD86 在多发性骨髓瘤中的作用
  • 批准号:
    9198507
  • 财政年份:
    2015
  • 资助金额:
    $ 21.51万
  • 项目类别:
Novel Roles for Effector Procaspases
效应器蛋白酶原的新作用
  • 批准号:
    9042395
  • 财政年份:
    2014
  • 资助金额:
    $ 21.51万
  • 项目类别:
Novel Roles for Effector Procaspases
效应器蛋白酶原的新作用
  • 批准号:
    8896823
  • 财政年份:
    2014
  • 资助金额:
    $ 21.51万
  • 项目类别:
Arsenic-induced apoptosis in myeloma
砷诱导骨髓瘤细胞凋亡
  • 批准号:
    7751820
  • 财政年份:
    2009
  • 资助金额:
    $ 21.51万
  • 项目类别:
Arsenic-induced apoptosis in myeloma
砷诱导骨髓瘤细胞凋亡
  • 批准号:
    8386638
  • 财政年份:
    2009
  • 资助金额:
    $ 21.51万
  • 项目类别:

相似国自然基金

染色体17p缺失淋巴瘤中脂肪酸代谢异常的调控机制及转化研究
  • 批准号:
    82130007
  • 批准年份:
    2021
  • 资助金额:
    290 万元
  • 项目类别:
    重点项目
TP53/17p杂合性缺失促进结直肠癌免疫逃逸的分子机制研究
  • 批准号:
  • 批准年份:
    2020
  • 资助金额:
    55 万元
  • 项目类别:
    面上项目
染色体大片段缺失的急性髓性白血病动物模型的构建及分析
  • 批准号:
    81770157
  • 批准年份:
    2017
  • 资助金额:
    84.0 万元
  • 项目类别:
    面上项目
P53基因去甲基化对del(17p)骨髓瘤细胞化疗药物敏感性的影响及其机制研究
  • 批准号:
    81600179
  • 批准年份:
    2016
  • 资助金额:
    18.0 万元
  • 项目类别:
    青年科学基金项目
染色体18q和17p上中国人膀胱癌相关基因的鉴定
  • 批准号:
    30170432
  • 批准年份:
    2001
  • 资助金额:
    20.0 万元
  • 项目类别:
    面上项目

相似海外基金

A combination strategy to target pathophysiology of chronic lymphocytic leukemia
针对慢性淋巴细胞白血病病理生理学的组合策略
  • 批准号:
    10577652
  • 财政年份:
    2023
  • 资助金额:
    $ 21.51万
  • 项目类别:
Predictive markers for personalized therapy in chronic lymphocytic leukemia
慢性淋巴细胞白血病个体化治疗的预测标记
  • 批准号:
    10591089
  • 财政年份:
    2023
  • 资助金额:
    $ 21.51万
  • 项目类别:
Defining the landscape of structural alterations in African American Multiple Myeloma
定义非裔美国人多发性骨髓瘤的结构改变
  • 批准号:
    10510606
  • 财政年份:
    2022
  • 资助金额:
    $ 21.51万
  • 项目类别:
Project 2: Defining and exploiting genetic dependencies in complex karyotype AML
项目 2:定义和利用复杂核型 AML 中的遗传依赖性
  • 批准号:
    10474281
  • 财政年份:
    2021
  • 资助金额:
    $ 21.51万
  • 项目类别:
Formulation, Evaluation, and Phase 0 Trial of Nanoparticle Releasing Oral Thin Film for OSCC Chemoprevention
用于口腔鳞癌化学预防的纳米颗粒释放口腔薄膜的配方、评估和 0 期试验
  • 批准号:
    10540811
  • 财政年份:
    2021
  • 资助金额:
    $ 21.51万
  • 项目类别:
Formulation, Evaluation, and Phase 0 Trial of Nanoparticle Releasing Oral Thin Film for OSCC Chemoprevention
用于口腔鳞癌化学预防的纳米颗粒释放口腔薄膜的配方、评估和 0 期试验
  • 批准号:
    10359559
  • 财政年份:
    2021
  • 资助金额:
    $ 21.51万
  • 项目类别:
Functional characterization of 2q22.1 deletion in oral squamous cell carcinoma
口腔鳞状细胞癌2q22.1缺失的功能特征
  • 批准号:
    10669010
  • 财政年份:
    2020
  • 资助金额:
    $ 21.51万
  • 项目类别:
Interplay between low levels of GAS7 expression and MYCN overexpression and its impact on neuroblastoma metastasis
GAS7低水平表达与MYCN过表达之间的相互作用及其对神经母细胞瘤转移的影响
  • 批准号:
    10213671
  • 财政年份:
    2020
  • 资助金额:
    $ 21.51万
  • 项目类别:
Functional characterization of 2q22.1 deletion in oral squamous cell carcinoma
口腔鳞状细胞癌2q22.1缺失的功能特征
  • 批准号:
    10285990
  • 财政年份:
    2020
  • 资助金额:
    $ 21.51万
  • 项目类别:
Interplay between low levels of GAS7 expression and MYCN overexpression and its impact on neuroblastoma metastasis
GAS7低水平表达与MYCN过表达之间的相互作用及其对神经母细胞瘤转移的影响
  • 批准号:
    10427275
  • 财政年份:
    2020
  • 资助金额:
    $ 21.51万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了