The B cell architecture of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is complex since it is composed of malignant lymphocyte-predominant (LP) cells along with a B cell rich bystander environment. To gain insight into molecular determinants of transformation, we studied B cell evolutionary trajectories in lymphoma tissue from diagnosis to relapse or transformation to non-Hodgkin lymphoma by immunoglobulin heavy chain next-generation sequencing. NLPHL cases that later transformed showed higher age, IgD negativity, absence of the characteristic IGHV3/IGHD3/IGHJ6 LP rearrangement and high repertoire clonality. We constructed phylogenetic trees within the compartment of the malignant clone to investigate clonal evolution. In all relapsing cases, the LP rearrangement was identical at diagnosis and relapse. NLPHL cases with transformation showed more complex trajectories with strong intraclonal diversification. The dominant founder clone in transformations showed clonal evolution, if derived from the same cell of origin, or originated from a different cell of origin. Together, our data point to a significant role of antigenic drive in NLHPL transformations and identify high B cell repertoire clonality with dominant intraclonal LP cell diversification as a hallmark of transformation. Sequencing of the initial paraffin-embedded tissue may therefore be diagnostically applied to identify NLPHL cases with high transformation risk.
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