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

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.

• Authors: 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, Tannishtha Reya
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 5998 (11 26 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 33243988 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Integrin beta Chains
• Msi2h protein, mouse
• RNA-Binding Proteins
• Sdc1 protein, mouse
• Syndecan-1
• integrin beta7
• Green Fluorescent Proteins
• Imatinib Mesylate

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Blast Crisis (genetics, pathology, therapy)
• Chemoradiotherapy (methods)
• Disease Models, Animal
• Drug Resistance, Neoplasm (drug effects)
• Gene Knock-In Techniques
• Gene Knockout Techniques
• Genes, Reporter (genetics)
• Green Fluorescent Proteins (chemistry, genetics)
• High-Throughput Screening Assays
• Humans
• Imatinib Mesylate (pharmacology, therapeutic use)
• Integrin beta Chains (metabolism)
• Leukemia, Myeloid, Acute (genetics, pathology, therapy)
• Mice, Transgenic
• Neoplastic Stem Cells (drug effects, pathology, radiation effects)
• RNA-Binding Proteins (genetics)
• RNA-Seq
• Signal Transduction (drug effects)
• Syndecan-1 (antagonists & inhibitors, genetics, metabolism)