CLL intraclonal fractions exhibit established and recently acquired patterns of DNA methylation
| Autor: | Jacqueline C. Barrientos, Nicholas Chiorazzi, Jose A. Martinez-Climent, Marien Pascual, Kanti R. Rai, Matthew D. Scharff, Xiao-Jie Yan, Boris Bartholdy, Manxia Fan, Sergio Roa, Xiahoua Wang, Steven L. Allen |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Mutation B-Lymphocytes Immunobiology and Immunotherapy Chronic lymphocytic leukemia Clone (cell biology) Hematology Methylation Biology DNA Methylation medicine.disease_cause medicine.disease Leukemia Lymphocytic Chronic B-Cell 03 medical and health sciences 030104 developmental biology 0302 clinical medicine 030220 oncology & carcinogenesis DNA methylation medicine Cancer research Humans Epigenetics CD5 IGHV@ |
| Zdroj: | Blood advances. 4(5) |
| ISSN: | 2473-9537 |
| Popis: | Intraclonal subpopulations of circulating chronic lymphocytic leukemia (CLL) cells with different proliferative histories and reciprocal surface expression of CXCR4 and CD5 have been observed in the peripheral blood of CLL patients and named proliferative (PF), intermediate (IF), and resting (RF) cellular fractions. Here, we found that these intraclonal circulating fractions share persistent DNA methylation signatures largely associated with the mutation status of the immunoglobulin heavy chain locus (IGHV) and their origins from distinct stages of differentiation of antigen-experienced B cells. Increased leukemic birth rate, however, showed a very limited impact on DNA methylation of circulating CLL fractions independent of IGHV mutation status. Additionally, DNA methylation heterogeneity increased as leukemic cells advanced from PF to RF in the peripheral blood. This frequently co-occurred with heterochromatin hypomethylation and hypermethylation of Polycomb-repressed regions in the PF, suggesting accumulation of longevity-associated epigenetic features in recently born cells. On the other hand, transcriptional differences between paired intraclonal fractions confirmed their proliferative experience and further supported a linear advancement from PF to RF in the peripheral blood. Several of these differentially expressed genes showed unique associations with clinical outcome not evident in the bulk clone, supporting the pathological and therapeutic relevance of studying intraclonal CLL fractions. We conclude that independent methylation and transcriptional landscapes reflect both preexisting cell-of-origin fingerprints and more recently acquired hallmarks associated with the life cycle of circulating CLL cells. |
| Databáze: | OpenAIRE |
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