Molecular Determinants of Sensitivity to Polatuzumab Vedotin in Diffuse Large B-Cell Lymphoma.

Autor:	Corcoran SR; Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, Maryland.; Wellcome MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.; Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts., Phelan JD; Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, Maryland., Choi J; Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, Maryland., Shevchenko G; Wellcome MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom., Fenner RE; Wellcome MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom., Yu X; Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, Maryland., Scheich S; Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, Maryland., Hsiao T; Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, Maryland., Morris VM; Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, Maryland.; Department of Biology, Johns Hopkins University, Baltimore, Maryland., Papachristou EK; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom., Kishore K; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom., D'Santos CS; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom., Ji Y; Max-Planck-Institute for Multidisciplinary Sciences, Göttingen, Germany., Pittaluga S; Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland., Wright GW; Biometrics Research Program, National Cancer Institute, NIH, Bethesda, Maryland., Urlaub H; Max-Planck-Institute for Multidisciplinary Sciences, Göttingen, Germany., Pan KT; University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany., Oellerich T; University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany., Muppidi J; Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, Maryland., Hodson DJ; Wellcome MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom., Staudt LM; Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, Maryland.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2024 Sep 04; Vol. 14 (9), pp. 1653-1674.
DOI:	10.1158/2159-8290.CD-23-0802
Abstrakt:	Polatuzumab vedotin (Pola-V) is an antibody-drug conjugate directed to the CD79B subunit of the B-cell receptor (BCR). When combined with conventional immunochemotherapy, Pola-V improves outcomes in diffuse large B-cell lymphoma (DLBCL). To identify determinants of Pola-V sensitivity, we used CRISPR-Cas9 screening for genes that modulated Pola-V toxicity for lymphomas or the surface expression of its target, CD79B. Our results reveal the striking impact of CD79B glycosylation on Pola-V epitope availability on the lymphoma cell surface and on Pola-V toxicity. Genetic, pharmacological, and enzymatic approaches that remove sialic acid from N-linked glycans enhanced lymphoma killing by Pola-V. Pola-V toxicity was also modulated by KLHL6, an E3 ubiquitin ligase that is recurrently inactivated in germinal center derived lymphomas. We reveal how KLHL6 targets CD79B for degradation in normal and malignant germinal center B cells, thereby determining expression of the surface BCR complex. Our findings suggest precision medicine strategies to optimize Pola-V as a lymphoma therapeutic. Significance: These findings unravel the molecular basis of response heterogeneity to Pola-V and identify approaches that might be deployed therapeutically to enhance the efficacy of CD79B-specific tumor killing. In addition, they reveal a novel post-translational mechanism used by normal and malignant germinal center B cells to regulate expression of the BCR. See related commentary by Leveille, p. 1577 See related article by Meriranta et al. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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