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

ABSTRACT: 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 DLBCL. To identify molecular determinants of sensitivity to Pola-V, we used CRISPR-Cas9 screening for genes that modulated the toxicity of Pola-V for lymphomas or the surface expression of its target, CD79B. Our results reveal a 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 terminal sialic acid residues from N-linked glycans enhanced lymphoma killing by Pola-V. Pola-V toxicity was also modulated by KLHL6, a ubiquitin ligase that targets CD79B for degradation in normal and malignant germinal center B cells, explaining its recurrent inactivation in germinal center-derived lymphomas. Our findings suggest precision medicine strategies to optimize Pola-V as a lymphoma therapeutic.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Evangelia Papachristou

LAB HEAD: Daniel J. Hodson

PROVIDER: PXD043670 | Pride | 2024-07-12

REPOSITORIES: pride

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			Action	DRS
	FP_ubiq_TMT_labelling.xlsx	Xlsx
	Lumos_FP_01.raw	Raw
	Lumos_FP_02.raw	Raw
	Lumos_FP_03.raw	Raw
	Lumos_FP_04.raw	Raw

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