A stem cell reporter based platform to identify and target drug resistant stem cells in myeloid leukemia
| Autor: | Nikki K. Lytle, Hyog Young Kwon, Michael Hamilton, Jeevisha Bajaj, Ferdous Anower-E-Khuda, Tannishtha Reya, Mark H. Ginsberg, Jeffrey D. Esko, Bryan Zimdahl, Armin Ahmadi, Kyle R. Spinler, Joi Weeks, Jan Karlseder, Claire S. Koechlein, Marcie Kritzik, Hao Sun, Pyong Woo Park, Allen Blevins, Takahiro Ito |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Myeloid Integrin beta Chains Drug Resistance General Physics and Astronomy Regenerative Medicine Transgenic Syndecan 1 Mice Gene Knockout Techniques 0302 clinical medicine Genes Reporter Stem Cell Research - Nonembryonic - Human Leukaemia 2.1 Biological and endogenous factors Gene Knock-In Techniques RNA-Seq Aetiology lcsh:Science Cancer Pediatric Multidisciplinary Leukemia Cell adhesion molecule Cancer stem cells Myeloid leukemia RNA-Binding Proteins Chemoradiotherapy Hematology Leukemia Myeloid Acute medicine.anatomical_structure 030220 oncology & carcinogenesis Neoplastic Stem Cells Imatinib Mesylate Stem Cell Research - Nonembryonic - Non-Human Stem cell Signal Transduction Biotechnology Pediatric Research Initiative Pediatric Cancer Childhood Leukemia Science 1.1 Normal biological development and functioning Green Fluorescent Proteins Mice Transgenic Antineoplastic Agents Biology Acute General Biochemistry Genetics and Molecular Biology Article Cancer screening 03 medical and health sciences Rare Diseases Cancer stem cell Live cell imaging Underpinning research medicine Animals Humans Reporter Animal General Chemistry medicine.disease Stem Cell Research High-Throughput Screening Assays Disease Models Animal 030104 developmental biology Genes Drug Resistance Neoplasm Disease Models Cancer research Neoplasm lcsh:Q Syndecan-1 Blast Crisis |
| Zdroj: | Nature communications, vol 11, iss 1 Nature Communications Nature Communications, Vol 11, Iss 1, Pp 1-15 (2020) |
| Popis: | Intratumoral heterogeneity is a common feature of many myeloid leukemias and a significant reason for treatment failure and relapse. Thus, identifying the cells responsible for residual disease and leukemia re-growth is critical to better understanding how they are regulated. Here, we show that a knock-in reporter mouse for the stem cell gene Musashi 2 (Msi2) allows identification of leukemia stem cells in aggressive myeloid malignancies, and provides a strategy for defining their core dependencies. Specifically, we carry out a high throughput screen using Msi2-reporter blast crisis chronic myeloid leukemia (bcCML) and identify several adhesion molecules that are preferentially expressed in therapy resistant bcCML cells and play a key role in bcCML. In particular, we focus on syndecan-1, whose deletion triggers defects in bcCML growth and propagation and markedly improves survival of transplanted mice. Further, live imaging reveals that the spatiotemporal dynamics of leukemia cells are critically dependent on syndecan signaling, as loss of this signal impairs their localization, migration and dissemination to distant sites. Finally, at a molecular level, syndecan loss directly impairs integrin β7 function, suggesting that syndecan exerts its influence, at least in part, by coordinating integrin activity in bcCML. These data present a platform for delineating the biological underpinnings of leukemia stem cell function, and highlight the Sdc1-Itgβ7 signaling axis as a key regulatory control point for bcCML growth and dissemination. Identifying leukaemia stem cells (LSC) and defining how they drive tumourigenesis might aid in the treatment of disease. Here, the authors show that a reporter Musashi 2 can serve as a platform to effectively identify leukemic stem cells and it is used to define Syndecan-1 as a dependency for these aggressive, therapy resistant cells. |
| Databáze: | OpenAIRE |
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