CD98 Promotes Acute Myeloid Leukemia Initiation and Growth

Interactions between the tumor microenvironment (TME) and tumors in promoting tumor growth and dissemination have been heavily investigated in solid tumors, but less frequently in hematologic malignancies. One of the molecules which mediate tumor–TME interactions is the transmembrane glycoprotein CD98, which is elevated in solid tumors and is composed of a heavy chain, which interacts with integrins to mediate protumorigenic integrin signaling, and a light chain that mediates amino acid transport to regulate mTORC1 signaling. Because CD98 promotes B- and T-cell activation and proliferation, Bajaj, Konuma, and colleagues evaluated mouse models of acute myeloid leukemia (AML) to elucidate the role of CD98 in leukemogenesis. Deletion of CD98 reduced the proliferative and self-renewal capacities of normal hematopoietic stem cells (HSC) in nontumor mice and increased survival of mice with MLL-AF9;Nras^G12V–driven AML and AML-ETO9a;Nras^G12V–driven AML. Further, ablation of CD98 resulted in increased apoptosis in leukemia cells and a decreased frequency of phenotypic and functional c-Kit⁺ leukemic stem cells (LSC). Consistent with these findings, expression of CD98 was enriched in human CD34⁺ AML stem cells compared to CD34⁻ AML cells. Expression of chimeric CD98-CD69 proteins in CD98-null cells revealed that CD98-integrin–mediated signaling and CD98-mediated amino acid transport contributed to AML growth and LSC survival. Knockdown of CD98 in patient-derived AML cells resulted in decreased AML adhesion to endothelial cells and colony formation in vitro and reduced tumor burden in vivo. Similarly, in vivo treatment of patient-derived AML cells with a humanized anti-CD98 monoclonal antibody completely ablated the engraftment of transplanted AML and reduced the tumor burden of established AML. Together, these findings demonstrate how tumor–TME interactions drive leukemogenesis, provide insight into the role of CD98 in normal hematopoiesis and leukemia, and suggest that anti-CD98 therapies may be potentially effective treatments for patients with AML.

Bajaj J, Konuma T, Lytle NK, Kwon HY, Ablack JN, Cantor JM, et al. CD98-mediated adhesive signaling enables the establishment and propagation of acute myelogenous leukemia. Cancer Cell 2016 Oct 27 [Epub ahead of print].