Affiliation:
1. *Division of Hematology, The Ohio State University College of Medicine, Columbus, OH;
2. †Nationwide Children’s Hospital, Columbus, OH; and
3. ‡Center for Biostatistics, The Ohio State University College of Medicine, Columbus, OH
Abstract
Abstract
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia, but, despite advances in treatment, many patients still experience relapse. CLL cells depend on interactions with supportive cells, and nurse-like cells (NLCs) are the major such cell type. However, little is known about how NLCs develop. Here, we performed DNA methylation analysis of CLL patient–derived NLCs using the 850K Illumina array, comparing CD14+ cells at day 1 (monocytes) versus day 14 (NLCs). We found a strong loss of methylation in AP-1 transcription factor binding sites, which may be driven by MAPK signaling. Testing of individual MAPK pathways (MEK, p38, and JNK) revealed a strong dependence on MEK/ERK for NLC development, because treatment of patient samples with the MEK inhibitor trametinib dramatically reduced NLC development in vitro. Using the adoptive transfer Eµ-TCL1 mouse model of CLL, we found that MEK inhibition slowed CLL progression, leading to lower WBC counts and to significantly longer survival time. There were also lower numbers of mouse macrophages, particularly within the M2-like population. In summary, NLC development depends on MEK signaling, and inhibition of MEK leads to increased survival time in vivo. Hence, targeting the MEK/ERK pathway may be an effective treatment strategy for CLL.
Funder
HHS | NIH | National Cancer Institute
OSUCCC Leukemia Research Program Seed Award
Pelotonia Fellowship Program Award
National Cancer Institute CCSG
OSUCCC Startup Funding
Publisher
The American Association of Immunologists
Subject
Immunology,Immunology and Allergy
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