Dissecting the Roles and Requirements for RBM39 in Acute Myeloid Leukemia and Normal Hematopoiesis

剖析 RBM39 在急性髓系白血病和正常造血中的作用和要求

基本信息

  • 批准号:
    10686988
  • 负责人:
  • 金额:
    $ 24.16万
  • 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

PROJECT SUMMARY/ABSTRACT Research: RNA binding proteins (RBPs) regulate diverse cellular processes including transcription, translation, and regulation of gene expression, and are frequently dysregulated in cancers. Through an unbiased genetic screen aimed at identifying cancer-specific RBP dependencies, we recently identified a specific requirement for RBM39 in malignant myeloid cancers and that cancers bearing RNA splicing factor mutations as being particularly sensitive to the anti-cancer sulfonamides. RBM39 is an RBP that functions in RNA splicing and recently, a class of clinical-grade “anti-cancer sulfonamide” compounds were demonstrated to degrade RBM39 protein by co-opting the Ddb1/CUL4 ubiquitin-ligase complex as their mechanism of action. Thus, the primary goal of this project is to assess differential and tissue-specific requirements for RBM39 in normal hematopoiesis versus myeloid malignancies, and to assess requirements for RBM39 for leukemia initiation and maintenance. This proposal will utilize a novel conditional knockout (cKO) mouse for Rbm39 and several associated newly developed in vitro and in vivo murine models to pursue this goal. We expect these investigations to further our understanding of the role of RBM39 in normal physiology and cancer as well as provide new therapeutic insights into the on- and off-target toxicities of the anti-cancer sulfonamides. These goals are particularly timely given that several of these molecules have already proven excellent safety in multiple phase I/II trials and are now ripe for therapeutic testing in a patient population most likely to benefit from RBM39 degradation. Candidate: Dr. Sydney X. Lu is a graduating hematology & medical oncology fellow in the Department of Medicine at MSKCC. He aims to become an independent, tenure- track physician-scientist investigating the molecular pathogenesis of hematological malignancies through a combination of genetics, functional genomics, and murine modeling. Dr.Lu has outlined a five-year period of mentored training to strengthen his skills in functional genomics and disease modeling. This training period will be carried out under the mentorship of Dr. Omar Abdel-Wahab, a leader in the functional genomics of hematopoietic malignancies. Dr. Lu has also assembled an advisory committee composed of Drs. Ross Levine, Martin Tallman, Michael Kharas, and Christine Mayr who will help guide his training and research. Environment: MSKCC is the world's oldest and largest private cancer center, devoting more than 130 years to exceptional patient care, innovative research, and outstanding educational programs. MSKCC exposes trainees to an exceptionally robust academic research environment with a strong commitment and track record of successfully supporting junior faculty who are seeking careers as independent physician-scientists.
项目总结/文摘

项目成果

期刊论文数量(0)
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Sydney X Lu其他文献

Adoptive transfer of in vitro generated T cell precursors improves T cell reconstitution and mediates graft-versus-tumor activity without graft-versus-host disease in allogeneic hematopoietic stem cell transplantation recipients
体外生成的 T 细胞前体的过继转移可改善同种异体造血干细胞移植受者的 T 细胞重建并介导移植物抗肿瘤活性,而不会出现移植物抗宿主病
  • DOI:
    10.1016/j.bbmt.2005.11.255
  • 发表时间:
    2006
  • 期刊:
  • 影响因子:
    4.3
  • 作者:
    J. Zakrzewski;Adam A. Kochman;Sydney X Lu;T. Terwey;T. Kim;Vanessa M. Hubbard;S. Muriglan;David Y. Suh;Javier Cabrera;G. Heller;J. Zúñiga;O. Alpdogan;M. Brink
  • 通讯作者:
    M. Brink
Targeted ‘Off-the-Shelf’ Tumor Immunotherapy Using Allogeneic T-Cell Precursors.
使用同种异体 T 细胞前体进行靶向“现成”肿瘤免疫治疗。
  • DOI:
    10.1182/blood.v110.11.579.579
  • 发表时间:
    2007
  • 期刊:
  • 影响因子:
    20.3
  • 作者:
    J. Zakrzewski;David Y. Suh;Odette M. Smith;Christopher G. King;G. Goldberg;R. Jenq;A. Holland;J. Grubin;Sydney X Lu;Javier Cabrera;G. Rizzuto;D. Sant’Angelo;M. Brink;J. C. Markley;I. Rivière;M. Sadelain;J. Zúñiga
  • 通讯作者:
    J. Zúñiga
CEACAM-1 Is Involved in Graft-Versus-Host-Disease in Murine Allogeneic Bone Marrow Transplantation Models.
CEACAM-1 参与小鼠同种异体骨髓移植模型中的移植物抗宿主病。
  • DOI:
    10.1182/blood.v110.11.67.67
  • 发表时间:
    2007
  • 期刊:
  • 影响因子:
    20.3
  • 作者:
    Sydney X Lu;Lucy M. Willis;Marsinay Smith;David Y. Suh;Christopher G. King;J. L. Bautista;Melanie Chow;Javier Cabrera;Vanessa M. Hubbard;J. Rotolo;Chen Liu;G. Murphy;O. Alpdogan;R. Blumberg;K. Holmes;C. Turbide;N. Beauchemin;M. Brink
  • 通讯作者:
    M. Brink
Depletion of Vascular Endothelial Progenitor Cells Simultaneously Ameliorates GVHD and Inhibits Tumor Growth
血管内皮祖细胞的消耗同时改善 GVHD 并抑制肿瘤生长
  • DOI:
  • 发表时间:
    2009
  • 期刊:
  • 影响因子:
    0
  • 作者:
    O. Penack;E. Henke;David Y. Suh;Christopher G. King;Marsinay Smith;Il;A. Holland;Arnab Ghosh;Sydney X Lu;R. Jenq;Chen Liu;C. May;G. Murphy;T. Lu;Dingcheng Gao;V. Mittal;R. Benezra;M. Brink
  • 通讯作者:
    M. Brink
Chemotherapy Signatures Map Evolution of Therapy-Related Myeloid Neoplasms
化疗特征图谱与治疗相关的骨髓肿瘤的演变
  • DOI:
    10.1101/2022.04.26.489507
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    0
  • 作者:
    B. Diamond;B. Ziccheddu;K. Maclachlan;Justin Taylor;E. Boyle;Juan Arrango Ossa;J. Jahn;Maurizio Affer;T. Totiger;D. Coffey;J. Watts;Sydney X Lu;N. Bolli;K. Bolton;Jae H. Park;H. Landau;K. Ganesh;A. McPherson;M. Sekeres;A. Lesokhin;D. Chung;Yanming Zhang;Caleb Ho;M. Roshal;J. Tyner;Stephen S. Nimer;E. Papaemmanuil;Saad Z. Usmani;G. Morgan;O. Landgren;F. Maura
  • 通讯作者:
    F. Maura

Sydney X Lu的其他文献

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{{ truncateString('Sydney X Lu', 18)}}的其他基金

Dissecting the Roles and Requirements for RBM39 in Acute Myeloid Leukemia and Normal Hematopoiesis
剖析 RBM39 在急性髓系白血病和正常造血中的作用和要求
  • 批准号:
    10615499
  • 财政年份:
    2022
  • 资助金额:
    $ 24.16万
  • 项目类别:

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    7902286
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    7691385
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