Ibrutinib downregulates a subset of miRNA leading to upregulation of tumor suppressors and inhibition of cell proliferation in chronic lymphocytic leukemia

Abstract

The lymph node (LN) is the site of chronic lymphocytic leukemia (CLL) cell activation and proliferation. Aberrant microRNA (miRNA) expression has been shown to have a role in CLL pathogenesis; however, a comparison of miRNA expression between CLL cells in the LN and the peripheral blood (PB) has previously not been reported. On the basis of the analysis of 17 paired LN and PB samples from CLL patients, we identify a panel of miRNAs that are increased in LN CLL cells correlating with an activation phenotype. When evaluated in CLL cells from 38 patients pre and post treatment with ibrutinib, a subset of these miRNAs (miR-22, miR-34a, miR-146b and miR-181b) was significantly decreased in response to ibrutinib. A concomitant increase in putative miRNA target transcripts (ARID1B, ARID2, ATM, CYLD, FOXP1, HDAC1, IBTK, PTEN and SMAD4) was also observed. Functional studies confirmed targets of ibrutinib-responsive miRNAs to include messenger RNA transcripts of multiple tumor suppressors. Knockdown of endogenous miR-34a and miR146b resulted in increased transcription of tumor suppressors and inhibition of cell proliferation. These findings demonstrate that ibrutinib downregulates the expression of a subset of miRNAs related to B-cell activation leading to increased expression of miRNA targets including tumor suppressors and a reduction in cell proliferation.

Synergistic effect of ibrutinib and CD19 CAR-T cells on Raji cells in vivo and in vitro

“…As a BTK inhibitor, ibrutinib controls the homing and migration of tumor cells by downregulating NF-кB signaling. It is important to block the interactions between macrophages and tumor cells [1][2][3][4].…”

Ibrutinib, a Bruton’s tyrosine kinase inhibitor, exhibits antitumoral activity and induces autophagy in glioblastoma

“…Ibrutinib, formerly known as PCI-32765, selectively and irreversibly inhibits BTK, and is administered once-daily to prevent B-cell differentiation, proliferation, and survival [7]. Ibrutinib exerts a potent anti-cancer effect by inhibiting BCR signaling and down-regulating NF-кB signaling, rapidly reducing tumor growth by inhibiting tumor proliferation and increasing apoptosis [8–10]. Recently, ibrutinib has also been used as a novel anticancer drug for several other types of cancers, such as human ovarian, breast, and lung cancer, and also gastric carcinoma, and glioma [11–14].…”

High expression of ETS2 predicts poor prognosis in acute myeloid leukemia and may guide treatment decisions

“…Up-regulation of miR - 155 was an independent risk factor associated with an unfavorable clinical outcome in cytogenetically normal-AML (CN-AML) [3]. Knockdown of endogenous miR - 146b would result in increased transcription of tumor suppressors and inhibition of cell proliferation in chronic lymphocytic leukemia (CLL) [27]. MiR - 1 - 2 modulation was vital for EVI1-associated tumor proliferation in acute myeloid leukemia [28].…”