A stem cell reporter based platform to identify and target drug resistant stem cells in myeloid leukemia

Kyle Spinler, Jeevisha Bajaj, Takahiro Ito, Bryan Zimdahl, Michael Hamilton, Armin Ahmadi, Claire S. Koechlein, Nikki Lytle, Hyog Young Kwon, Ferdous Anower-E-Khuda, Hao Sun, Allen Blevins, Joi Weeks, Marcie Kritzik, Jan Karlseder, Mark H. Ginsberg, Pyong Woo Park, Jeffrey D. Esko and Tannishtha Reya ()
Additional contact information
Kyle Spinler: University of California San Diego School of Medicine
Jeevisha Bajaj: University of California San Diego School of Medicine
Takahiro Ito: University of California San Diego School of Medicine
Bryan Zimdahl: University of California San Diego School of Medicine
Michael Hamilton: University of California San Diego School of Medicine
Armin Ahmadi: University of California San Diego School of Medicine
Claire S. Koechlein: University of California San Diego School of Medicine
Nikki Lytle: University of California San Diego School of Medicine
Hyog Young Kwon: University of California San Diego School of Medicine
Ferdous Anower-E-Khuda: University of California San Diego School of Medicine
Hao Sun: University of California San Diego
Allen Blevins: University of California San Diego School of Medicine
Joi Weeks: University of California San Diego School of Medicine
Marcie Kritzik: University of California San Diego School of Medicine
Jan Karlseder: Salk Institute
Mark H. Ginsberg: University of California San Diego
Pyong Woo Park: Boston Children’s Hospital, Harvard Medical School
Jeffrey D. Esko: University of California San Diego School of Medicine
Tannishtha Reya: University of California San Diego School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract 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.

Date: 2020
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-020-19782-x Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19782-x

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-020-19782-x

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().