A single-cell multi-omic and spatial atlas of B cell lymphomas reveals differentiation drives intratumor heterogeneity

Intratumor heterogeneity is intrinsic to cancer evolution and treatment resistance, although it is typically considered distinct from the differentiation processes driving cell-type and cancer-type diversity. Nodal B cell non-Hodgkin lymphomas are tied to distinct stages of B cell maturation. Through a single-cell multi-omic and spatial atlas of diffuse large B cell, mantle cell, follicular, and marginal zone lymphomas in addition to reactive lymph nodes in 51 patients, we uncovered co-existing B cell maturation states within the same tumors. These intratumor maturation states emerged from the same clone, revealing ongoing differentiation from the cell-of-origin. Maturation state composition varied across and within disease entities, with tumors encompassing mixed cell-of-origin clinical subtypes. Intratumor maturation states inhabited unique spatial niches, maintaining their maturation-associated cellular interactions and regulatory networks while harboring distinct genetic variant expression patterns. Our findings show that cell-type differentiation remains plastic in cancer and is central to tumor variation and evolution. ![Figure][1] ### Competing Interest Statement G.P.N. is a co-founder and stockholder of Akoya Biosciences, Inc. and inventor on patent US9909167 (On-slide staining by primer extension). [1]: pending:yes