Abstract
Abstract Chronic lymphocytic leukemia (CLL) is the most common adult leukemia, with the NIH estimating 20,720 new cases and 3,930 deaths in 2019. Despite advances in treatment, some patients still relapse (eg. up to 10 to 18% of ibrutinib-treated patients). CLL cells depend on interactions with supportive cells for survival, and nurse-like cells (NLCs) are the major such cell type. However, little is known about how NLCs develop. Thus, our objective is to elucidate NLC development for the purpose of identifying novel therapeutic targets that may aid in the treatment of CLL. We examined DNA methylation patterns of NLCs and found unusually strong MAPK and AP-1 transcription factor signatures. qPCR showed upregulation of MAF, MAFF and JUN in NLCs, supporting this epigenetics analysis. To test the role of the high MAPK signature we treated NLC cultures with inhibitors of Mek, p38 or Jnk. Results showed that Mek inhibition dramatically reduced NLC development. Of note, we did not detect phosphorylated Erk in CLL cells within treated or control cultures, suggesting that the Mek inhibitor acted directly against the CD14+-derived cells. We then tested Mek inhibition in vivo with the Eμ-TCL1 mouse model of CLL and found that it led to significantly longer survival time and lower white-blood-cell counts. In conclusion, we found that NLC development is dependent on Mek signaling and that Mek inhibition extends survival in vivo. This suggests that targeting the Mek/Erk pathway may be an effective treatment strategy for CLL.
Published Version
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