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Preneoplastic Alterations Define CLL DNA Methylome and Persist through Disease Progression and Therapy BLOOD CANCER DISCOVERY Kretzmer, H., Biran, A., Purroy, N., Lemvigh, C. K., Clement, K., Gruber, M., Gu, H., Rassenti, L., Mohammad, A. W., Lesnick, C., Slager, S. L., Braggio, E., Shanafelt, T. D., Kay, N. E., Fernandes, S. M., Brown, J. R., Wang, L., Li, S., Livak, K. J., Neuberg, D. S., Klages, S., Timmermann, B., Kipps, T. J., Campo, E., Gnirke, A., Wu, C. J., Meissner, A. 2021; 2 (1): 54-69

Abstract

Most human cancers converge to a deregulated methylome with reduced global levels and elevated methylation at select CpG islands. To investigate the emergence and dynamics of the cancer methylome, we characterized genome-wide DNA methylation in pre-neoplastic monoclonal B cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL), including serial samples collected across disease course. We detected the aberrant tumor-associated methylation landscape at CLL diagnosis and found no significantly differentially methylated regions in the high-count MBL-to-CLL transition. Patient methylomes showed remarkable stability with natural disease and post-therapy progression. Single CLL cells were consistently aberrantly methylated, indicating a homogeneous transition to the altered epigenetic state, and a distinct expression profile together with MBL cells compared to normal B cells. Our longitudinal analysis reveals the cancer methylome to emerge early, which may provide a platform for subsequent genetically-driven growth dynamics and together with its persistent presence suggests a central role in the normal-to-cancer transition.

View details for DOI 10.1158/2643-3230.BCD-19-0058

View details for Web of Science ID 000727266900002

View details for PubMedID 33604581

View details for PubMedCentralID PMC7888194