The regulatory interaction of EVI1 with the TCL1A oncogene impacts cell survival and clinical outcome in CLL

Abstract

Dysregulated T-cell leukemia/lymphoma-1A (TCL1A), a modulator in B-cell receptor (BCR) signaling, is causally implicated in chronic lymphocytic leukemia (CLL). However, the mechanisms of the perturbed TCL1A regulation are largely unknown. To characterize TCL1A-upstream networks, we functionally screened for TCL1A-repressive micro-RNAs (miRs) and their transcriptional regulators. We identified the novel miR-484 to target TCL1A's 3'-UTR and to be downregulated in CLL. In chromatin immunoprecipitations and reporter assays, the oncogenic transcription factor of myeloid cells, EVI1, bound and activated the miR-484 promoter. Most common in CLL was a pan-EVI1 transcript variant. EVI1 protein expression revealed distinct normal-tissue and leukemia-associated patterns of EVI1/TCL1A co-regulation. EVI1 levels were particularly low in TCL1A-high CLL or such cellular subsets. Global gene expression profiles from a 337-patient set linked EVI1 networks to BCR signaling and cell survival via TCL1A, BTK and other molecules of relevance in CLL. Enforced EVI1, as did miR-484, repressed TCL1A. Furthermore, it reduced phospho-kinase levels, impaired cell survival, mitigated BCR-induced Ca-flux and diminished the in vitro ibrutinib response. Moreover, TCL1A and EVI1 showed a strongly interactive hazard prediction in prospectively treated patients. Overall, we present regressive EVI1 as a novel regulatory signature in CLL. Through enhanced TCL1A and other EVI1-targeted hallmarks of CLL, this contributes to an aggressive cellular and clinical phenotype.

The γ-secretase inhibitors enhance the anti-leukemic activity of ibrutinib in B-CLL cells

“…Cell cultures obtained from the same cohort of B-CLL patients (Table 1 ) were exposed in vitro to Ibrutinib, used at the concentration corresponding to the IC 50 mean value determined in previous studies of our group in primary B-CLL cultures [ 11 ] and in line with other groups [ 20 – 23 ]. As shown in Figure 2A , in vitro treatment with Ibrutinib revealed a progressive reduction of cell viability coupled to the induction of apoptosis, with mean±SD (percentage of apoptotic cells over basal levels) of 18±12 and 32±15 at 24 and 48 hours of treatment, respectively.…”

lncRNA Ttc3-209 Promotes the Apoptosis of Retinal Ganglion Cells in Retinal Ischemia Reperfusion Injury by Targeting the miR-484/Wnt8a Axis

“…A number of studies support the antiapoptotic function of miR-484 in a variety of cells. 18,[43][44][45][46][47] However, another previous study reported that the suppression of lncRNA H19 significantly reduced the viability of A549 cell viability, migration, and invasion but promoted apoptosis by targeting miR-484 in human lung cancer cells. 48 In this study, we found that the overexpression of miR-484 attenuated the apoptosis of RGCs induced by I/R damage; this opposed the effects arising from lncRNA Ttc3-209 treatment (Fig.…”

The role of EVI-1 in normal hematopoiesis and myeloid malignancies (Review)

“…Overall, the regressive EVI-1 is a novel regulatory signature in CLL. Through enhanced TCL1A and other EVI-1-targeted hallmarks of CLL, this contributes to an aggressive cellular and clinical phenotype (65,66).…”