CD98-Mediated Adhesive Signaling Enables the Establishment and Propagation of Acute Myelogenous Leukemia

Jeevisha Bajaj; Takaaki Konuma; Nikki K Lytle; Hyog Young Kwon; Jailal N Ablack; Joseph M Cantor; David Rizzieri; Charles Chuah; Vivian G Oehler; Elizabeth H Broome; Edward D Ball; Edward H van der Horst; Mark H Ginsberg; Tannishtha Reya

doi:10.1016/j.ccell.2016.10.003

CD98-Mediated Adhesive Signaling Enables the Establishment and Propagation of Acute Myelogenous Leukemia

Cancer Cell. 2016 Nov 14;30(5):792-805. doi: 10.1016/j.ccell.2016.10.003. Epub 2016 Oct 27.

Authors

Affiliations

¹ Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA; Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA 92093, USA; Department of Medicine, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
² Department of Medicine, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
³ Division of Cell Therapy, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
⁴ Department of Haematology, Singapore General Hospital, Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore 169857, Singapore.
⁵ Clinical Research Division, Fred Hutchinson Cancer Research Center, WA 98109, USA.
⁶ Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA 92093, USA; Department of Pathology, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
⁷ Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA 92093, USA; Department of Medicine, Blood and Marrow Transplantation Division, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
⁸ Igenica Biotherapeutics Inc., Burlingame, CA 94010, USA.
⁹ Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA 92093, USA; Department of Medicine, University of California San Diego School of Medicine, La Jolla, CA 92093, USA. Electronic address: [email protected].
¹⁰ Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA; Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA 92093, USA; Department of Medicine, University of California San Diego School of Medicine, La Jolla, CA 92093, USA. Electronic address: [email protected].

Abstract

Acute myelogenous leukemia (AML) is an aggressive disease associated with drug resistance and relapse. To improve therapeutic strategies, it is critical to better understand the mechanisms that underlie AML progression. Here we show that the integrin binding glycoprotein CD98 plays a central role in AML. CD98 promotes AML propagation and lethality by driving engagement of leukemia cells with their microenvironment and maintaining leukemic stem cells. Further, delivery of a humanized anti-CD98 antibody blocks growth of patient-derived AML, highlighting the importance of this pathway in human disease. These findings indicate that microenvironmental interactions are key regulators of AML and that disrupting these signals with targeted inhibitors such as CD98 antibodies may be a valuable therapeutic approach for adults and children with this disease.

Keywords: CD98; SLC3A2; acute myelogenous leukemia; adhesion; cancer; cancer stem cell; imaging; integrin; leukemia; microenvironment.

Publication types

Comment

MeSH terms

Animals
Antibodies / administration & dosage*
Antibodies / pharmacology
Cell Adhesion
Cell Line, Tumor
Cell Proliferation / drug effects
Fusion Regulatory Protein-1 / antagonists & inhibitors
Fusion Regulatory Protein-1 / genetics*
Gene Knockout Techniques
Humans
Leukemia, Myeloid, Acute / drug therapy*
Leukemia, Myeloid, Acute / genetics
Leukemia, Myeloid, Acute / pathology
Mice
Neoplasm Transplantation
Neoplastic Stem Cells / pathology*

Substances

Antibodies
Fusion Regulatory Protein-1

Abstract

Publication types

MeSH terms

Substances

Grants and funding