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

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

doi:10.1016/j.ccell.2016.10.003

Cited by 96 publications

(100 citation statements)

References 56 publications

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“…This supports the idea that most anti-CD98 antibodies act through antibody-dependent cellular cytotoxicity (ADCC) (60), rather than by inhibiting amino acid transport per se. Nonetheless, these antibodies may still block the binding of known partners to the ED (62,63). The recently characterized humanized antibody, IGN523, exhibits robust anti-tumor activity through ADCC (60), and its epitopes are predicted to be different from those presented here.…”

Section: Anti-cd98 Antibodies and Epitopesmentioning

confidence: 91%

Cryo-EM structure of the human L-type amino acid transporter 1 in complex with glycoprotein CD98hc

Lee

Wiriyasermkul

Jin

et al. 2019

Preprint

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The L-type amino acid transporter 1 (LAT1) transports large neutral amino acids and drugs across the plasma membrane and is crucial for nutrient uptake, brain drug delivery and tumor growth. LAT1 is a unique solute carrier that forms a disulfide-linked heterodimer with the cell-surface glycoprotein CD98 heavy chain (CD98hc), but the mechanisms of its molecular assembly and amino acid transport are poorly understood.Here we report the cryo-EM structure of the human LAT1-CD98hc heterodimer at 3.4 Å resolution, revealing the hitherto unprecedented architecture of a solute carrier-glycoprotein heterocomplex. LAT1 features a canonical LeuT-fold while exhibiting an unusual loop structure on transmembrane helix 6, creating an extended cavity to accommodate bulky hydrophobic amino acids and drugs. CD98hc engages with LAT1 through multiple interactions, not only in the extracellular and transmembrane domains but also in the interdomain linker. The heterodimer interface features multiple sterol molecules, corroborating previous biochemical data on the role of cholesterols in heterodimer stabilization. We also visualized the binding modes of two anti-CD98 antibodies and show that they recognize distinct, multiple epitopes on CD98hc but not its glycans, explaining their robust reactivities despite the glycan heterogeneity. Furthermore, we mapped disease-causing mutations onto the structure and homology models, which rationalized some of the phenotypes of SLC3-and SLC7-related congenital disorders. Together, these results shed light on the principles of the structural assembly between a glycoprotein and a solute carrier, and provide a template for improving preclinical drugs and therapeutic antibodies targeting LAT1 and CD98.

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Section: Anti-cd98 Antibodies and Epitopesmentioning

confidence: 91%

Cryo-EM structure of the human L-type amino acid transporter 1 in complex with glycoprotein CD98hc

Lee

Wiriyasermkul

Jin

et al. 2019

Preprint

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“…l ‐Type amino acid transporter 1 (LAT1) is the first identified CD98lc, and cancers from several tissues express both CD98hc and LAT1 proteins. The oncogenicity of CD98 was confirmed with wild‐type CD98hc bound to CD98lc, but not with mutated CD98hc lacking the cysteine residue needed for the association with CD98lc.…”

Section: Introductionmentioning

confidence: 99%

“…Although the major targets of existing anticancer therapeutic antibodies are receptor‐type tyrosine kinases, overexpression of anti‐HER1 and anti‐HER2 is limited to cancers from squamous or glandular epithelium, respectively. As CD98/LAT1 is expressed by almost all cancers irrespective of tissue origin, anti‐CD98/LAT1 therapeutic antibodies may be ideal against numerous human malignancies.…”

Section: Introductionmentioning

confidence: 99%

Anti‐tumor effects of mAb against l‐type amino acid transporter 1 (LAT1) bound to human and monkey LAT1 with dual avidity modes

Ueda

Hayashi²,

Miyamoto

et al. 2019

Cancer Science

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l‐Type amino acid transporter 1 (LAT1) disulfide linked to CD98 heavy chain (hc) is highly expressed in most cancer cells, but weakly expressed in normal cells. In the present study, we developed novel anti‐LAT1 mAbs and showed internalization activity, inhibitory effects of amino acid uptake and cell growth and antibody‐dependent cellular cytotoxicity, as well as in vivo antitumor effects in athymic mice. Furthermore, we examined the reactivity of mAbs with LAT1 of Macaca fascicularis to evaluate possible side‐effects of antihuman LAT1 mAbs in clinical trials. Antihuman LAT1 mAbs reacted with ACHN human and MK.P3 macaca kidney‐derived cells, and this reactivity was significantly decreased by siRNAs against LAT1. Macaca LAT1 cDNA was cloned from MK.P3, and only two amino acid differences between human and macaca LAT1 were seen. RH7777 rat hepatoma and HEK293 human embryonic kidney cells expressing macaca LAT1 were established as stable transfectants, and antihuman LAT1 mAbs were equivalently reactive against transfectants expressing human or macaca LAT1. Dual (high and low) avidity modes were detected in transfectants expressing macaca LAT1, MK.P3, ACHN and HCT116 human colon cancer cells, and KA values were increased by anti‐CD98hc mAb, suggesting anti‐LAT1 mAbs detect an epitope on LAT1‐CD98hc complexes on the cell surface. Based on these results, LAT1 may be a promising anticancer target and Macaca fascicularis can be used in preclinical studies with antihuman LAT1 mAbs.

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“…In general, the overexpression of CD98 is associated with poor prognosis for cancer patients, thus rendering it a promising tumor target for diagnosis and therapy. Indeed, treatment of patient‐derived AML cells and of established human lymphoma cell lines with a clinical stage humanized anti‐CD98hc monoclonal antibody (mAb IGN523) was shown to block cancer growth in xenograft studies …”

Section: Introductionmentioning

confidence: 99%

“…Indeed, treatment of patient-derived AML cells and of established human lymphoma cell lines with a clinical stage humanized anti-CD98hc monoclonal antibody (mAb IGN523) was shown to block cancer growth in xenograft studies. 12 Beyond implications for cancer therapy, recent studies identified CD98hc as a novel transcytosis receptor at the blood-brain barrier (BBB), which appears suitable for the noninvasive drug delivery to the brain via the molecular Trojan horse strategy. 13,14 In this approach, the transport of a systemically administered therapeutic agent across the BBB into the parenchyma is enabled by fusion with a specific binding protein for the transcytosis receptor.…”

Section: Introductionmentioning

confidence: 99%

Structural differences between the ectodomains of murine and human CD98hc

2019

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The CD98 heavy chain (CD98hc) constitutes both a promising cell surface target for the treatment of cancers and a transcytosis receptor potentially useful for the brain delivery of therapeutics. However, pharmacokinetic studies and safety assessment of cognate antibodies or nonimmunoglobulin binding proteins in rodents is hampered by cross‐species variability of both amino acid sequence and glycosylation pattern. Here, we report the crystal structure of the murine CD98hc extracellular domain and a comprehensive comparison with its human ortholog, revealing only one conserved surface patch that is neither shielded by glycosylation nor by the cell membrane with an accessible surface area typical for an antibody epitope. Our results imply the necessity of a surrogate approach for CD98hc‐specific binding proteins with predictive power for clinical investigations.

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

Cited by 96 publications

References 56 publications

Cryo-EM structure of the human L-type amino acid transporter 1 in complex with glycoprotein CD98hc

Cryo-EM structure of the human L-type amino acid transporter 1 in complex with glycoprotein CD98hc

Anti‐tumor effects of mAb against l‐type amino acid transporter 1 (LAT1) bound to human and monkey LAT1 with dual avidity modes

Structural differences between the ectodomains of murine and human CD98hc

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