Preneoplastic Alterations Define CLL DNA Methylome and Persist through Disease Progression and Therapy

Helene Kretzmer, Anat Biran, Noelia Purroy, Camilla K. Lemvigh, Kendell Clement, Michaela Gruber, Hongcang Gu, Laura Rassenti, Arman W. Mohammad, Connie Lesnick, Susan L. Slager, Esteban Braggio, Tait D. Shanafelt, Neil E. Kay, Stacey M. Fernandes, Jennifer R. Brown, Lili Wang, Shuqiang Li, Kenneth J. Livak, Donna S. NeubergSven Klages, Bernd Timmermann, Thomas J. Kipps, Elias Campo, Andreas Gnirke, Catherine J. Wu*, Alexander Meissner*

*Corresponding author for this work

Research output: Contribution to journalComment/debateResearchpeer-review


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 preneoplastic 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 significant differentially methylated regions in the high-count MBL-to-CLL transition. Patient methylomes showed remarkable stability with natural disease and posttherapy 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 with 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 disease onset. SIGNIFICANCE: DNA methylation data from a large cohort of patients with MBL and CLL show that epigenetic transformation emerges early and persists throughout disease stages with limited subsequent changes. Our results indicate an early role for this aberrant landscape in the normal-to-preneoplastic transition that may reflect a pan-cancer mechanism.
Original languageEnglish
JournalCancer Discovery
Issue number1
Pages (from-to)54-69
Publication statusPublished - 2021


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