DUSP4 deficiency caused by promoter hypermethylation drives JNK signaling and tumor cell survival in diffuse large B cell lymphoma.
Bottom Line: The epigenetic dysregulation of tumor suppressor genes is an important driver of human carcinogenesis.We find that a CpG island in the promoter of the dual-specificity phosphatase DUSP4 is aberrantly methylated in nodal and extranodal DLBCL, irrespective of ABC or GCB subtype, resulting in loss of DUSP4 expression in 75% of >200 examined cases.This finding provides a mechanistic basis for the clinical development of JNK inhibitors in DLBCL, ideally in synthetic lethal combinations with inhibitors of chronic active B cell receptor signaling.
Affiliation: Institute of Molecular Cancer Research, Institute of Molecular Life Sciences, and Swiss Institute of Bioinformatics (SIB), University of Zürich, 8057 Zürich, Switzerland.Show MeSH
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Mentions: Ibrutinib is a novel inhibitor of BTK that has proven to be effective in ABC-DLBCL with chronic active BCR signaling in various preclinical combination treatments (Mathews Griner et al., 2014). To examine whether simultaneous JNK and BTK inhibition synergizes to kill DLBCL cells, we conducted single and combination treatments with SP600125 and ibrutinib. Ibrutinib treatment alone was insufficient to kill any of our DLBCL cell lines at concentrations up to 1 µM (Fig. 8 A). However, the addition of ibrutinib, even at very low doses of 1–10 nM, strongly boosted the efficacy of SP600125 in two ABC-DLBCL cell lines (Fig. 8, B and C). This effect was not seen in the GCB cell line SU-DHL16 (Fig. 8 D) or in an ABC-DLBCL cell line in which the BCR signaling pathway is constitutively active as the result of a CARD11 mutation (Oci-Ly3; Fig. 8 E). In those cell lines where ibrutinib augmented the effects of JNK inhibition, the two treatments were clearly synergistic, as determined by Chalice matrix analyses and the isobologram method (Fig. 8, F and G). In summary, our data indicate that JNK inhibitors should be considered for assessment as single agents in clinical trials for both subtypes of DLBCL and might be especially promising in combination with ibrutinib in ABC-DLBCL.
Affiliation: Institute of Molecular Cancer Research, Institute of Molecular Life Sciences, and Swiss Institute of Bioinformatics (SIB), University of Zürich, 8057 Zürich, Switzerland.