@article{5578a54520774ee2adcea8361ad397ba,
title = "Preneoplastic Alterations Define CLL DNA Methylome and Persist through Disease Progression and Therapy",
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 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.",
author = "Helene Kretzmer and Anat Biran and Noelia Purroy and Lemvigh, {Camilla K.} and Kendell Clement and Michaela Gruber and Hongcang Gu and Laura Rassenti and Mohammad, {Arman W.} and Connie Lesnick and Slager, {Susan L.} and Esteban Braggio and Shanafelt, {Tait D.} and Kay, {Neil E.} and Fernandes, {Stacey M.} and Brown, {Jennifer R.} and Lili Wang and Shuqiang Li and Livak, {Kenneth J.} and Neuberg, {Donna S.} and Sven Klages and Bernd Timmermann and Kipps, {Thomas J.} and Elias Campo and Andreas Gnirke and Wu, {Catherine J.} and Alexander Meissner",
note = "Funding Information: The authors thank members of the Meissner lab, in particular Jocelyn Charlton, and both Erin M. Parry and Inaki Subero-Martin for critical reading of the article. The authors thank Jerome Ritz and the DFCI Pasquarello Tissue Bank in Hematologic Malignancies for the prospective collection and processing of blood samples from healthy donors. This work was supported in part by the NCI (5P01CA081534-14). A. Biran was supported by the Lymphoma Research Foundation. C.K. Lemvigh acknowledges support from the Fishman Family Fund. M. Gruber received a Marie-Curie International Outgoing Fellowship from the European Union (PIOF-2013-624924). T.D. Shanafelt and N.E. Kay were supported by the NIH (R01CA197120). E. Campo is supported by Instituto de Salud Carlos III, Madrid Spain (PMP15/00007), “La Caixa” Foundation (grant CLLEvolution-HR17-00221), Health Research 2017, and European Research Council (ERC) BCLLatlas - 810287 and is a Researcher of the “Instituci{\'o} Catalana de Recerca i Estudis Avan{\c c}ats” (ICREA) of the Generalitat de Catalunya. S.L. Slager and E. Braggio were supported by R01 CA235026. J.R. Brown is supported by NCI RO1 CA 213442 and the Rosenbach Fund for Lymphoma Research. S. Li is supported by the NCI Research Specialist Award (R50CA251956-01). The single-cell analysis was supported by a SPARC grant of the Broad Institute (to A. Gnirke). C.J. Wu acknowledges support from the CLL Global Research Foundation, NHLBI (1RO1HL103532-01), and NCI (1R01CA155010-01A1 and UG1 CA233338), and is a Scholar of the Leukemia & Lymphoma Society. A. Meissner acknowledges support from the Starr Foundation, the New York Stem Cell Foundation, and the Max Planck Society. Publisher Copyright: {\textcopyright}2020 American Association for Cancer Research.",
year = "2021",
month = jan,
day = "1",
doi = "10.1158/2643-3230.BCD-19-0058",
language = "English (US)",
volume = "2",
pages = "54--69",
journal = "Blood cancer discovery",
issn = "2643-3230",
publisher = "NLM (Medline)",
number = "1",
}