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

Kyle Spinler1,2, Jeevisha Bajaj1,2, Takahiro Ito1,2, Bryan Zimdahl1,2,3, Michael Hamilton1,2, Armin Ahmadi1,2, Claire S Koechlein1,2, Nikki Lytle1,2, Hyog Young Kwon1,2, Ferdous Anower-E-Khuda4, Hao Sun5, Allen Blevins1,2, Joi Weeks1,2, Marcie Kritzik1,2, Jan Karlseder6, Mark H Ginsberg5, Pyong Woo Park7, Jeffrey D Esko4, Tannishtha Reya8,9,10,11

  1. Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA, USA.
  2. Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
  3. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
  4. Department of Cellular and Molecular Medicine, University of California San Diego School of Medicine, La Jolla, CA, USA.
  5. Department of Medicine, University of California San Diego, La Jolla, CA, USA.
  6. Salk Institute, La Jolla, CA, USA.
  7. Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  8. Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA, USA. treya@health.ucsd.edu.
  9. Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA. treya@health.ucsd.edu.
  10. Department of Medicine, University of California San Diego, La Jolla, CA, USA. treya@health.ucsd.edu.
  11. Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA, USA. treya@health.ucsd.edu.

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.

Presented By Kyle Spinler

Cancer BiologyNicholas Liao2020-11 (Nov)