Increased Expression of Bcl11b Leads to Chemoresistance Accompanied by G1 Accumulation

Abstract

BackgroundThe expression of BCL11B was reported in T-cells, neurons and keratinocytes. Aberrations of BCL11B locus leading to abnormal gene transcription were identified in human hematological disorders and corresponding animal models. Recently, the elevated levels of Bcl11b protein have been described in a subset of squameous cell carcinoma cases. Despite the rapidly accumulating knowledge concerning Bcl11b biology, the contribution of this protein to normal or transformed cell homeostasis remains open.Methodology/Principal FindingsHere, by employing an overexpression strategy we revealed formerly unidentified features of Bcl11b. Two different T-cell lines were forced to express BCL11B at levels similar to those observed in primary T-cell leukemias. This resulted in markedly increased resistance to radiomimetic drugs while no influence on death-receptor apoptotic pathway was observed. Apoptosis resistance triggered by BCL11B overexpression was accompanied by a cell cycle delay caused by accumulation of cells at G1. This cell cycle restriction was associated with upregulation of CDKN1C (p57) and CDKN2C (p18) cyclin dependent kinase inhibitors. Moreover, p27 and p130 proteins accumulated and the SKP2 gene encoding a protein of the ubiquitin-binding complex responsible for their degradation was repressed. Furthermore, the expression of the MYCN oncogene was silenced which resulted in significant depletion of the protein in cells expressing high BCL11B levels. Both cell cycle restriction and resistance to DNA-damage-induced apoptosis coincided and required the histone deacetylase binding N-terminal domain of Bcl11b. The sensitivity to genotoxic stress could be restored by the histone deacetylase inhibitor trichostatine A.ConclusionsThe data presented here suggest a potential role of BCL11B in tumor survival and encourage developing Bcl11b-inhibitory approaches as a potential tool to specifically target chemoresistant tumor cells.

The DN2 Myeloid-T (DN2mt) Progenitor is a Target Cell for Leukemic Transformation by the TLX1 Oncogene

“…Moreover, ectopic expression of BCL11B in the TLX1 + ALL-SIL T-ALL cell line conferred resistance to the topoisomerase IIα poison etoposide. In accord with other investigations [84,102], we found that BCL11B expression was associated with a reduced proliferation rate (unpublished data). Of relevance to our findings, Schmidt and colleagues reported that BCL11B overexpression in TLX1-negative T-ALL cell lines conferred resistance to etoposide-induced death through a mechanism associated with cell cycle delay at the G 1 /S phase [84].…”

“…In accord with other investigations [84,102], we found that BCL11B expression was associated with a reduced proliferation rate (unpublished data). Of relevance to our findings, Schmidt and colleagues reported that BCL11B overexpression in TLX1-negative T-ALL cell lines conferred resistance to etoposide-induced death through a mechanism associated with cell cycle delay at the G 1 /S phase [84]. In view of our earlier findings that TLX1 also stimulates G 1 /S progression [24], it will be interesting to determine whether a similar mechanism operates in TLX1 + T-ALL cells.…”

“…DP thymocytes normally express BCL11B, and Avram showed that BCL11B-deficient DP thymocytes are more prone to spontaneous cell death [82]. Studies in other systems have indicated that upregulation of BCL11B expression increases resistance to genotoxic stress in some circumstances [83,84]. As noted above, De Keersmaecker et al reported that BCL11B was repressed by TLX1 in ALL-SIL, becoming transcriptionally upregulated after TLX1 knockdown [12].…”

The role of BCL11B in hematological malignancy

“…A comparison of genome profiles of acute and lymphoma types revealed BCL11B over-expression in the acute form, regardless of the 14q32 gain/amplification, but either low or no levels of this gene’s expression in the lymphomas; these results suggest that acute and lymphoma types are genomically distinct subtypes, which thus may develop tumors via distinct genetic pathways [38]. Apoptosis resistance triggered by BCL11B over-expression was found to be accompanied by chemo-resistance caused by the accumulation of T-ALL cells in the G1 phase [39].…”

Integrated genome-wide genotyping and gene expression profiling reveals BCL11B as a putative oncogene in acute myeloid leukemia with 14q32 aberrations

“…[41][42][43][44][45] It was shown recently that the expression of BCL11B in T-cell lines resulted in markedly increased apoptosis resistance following treatment with radiomimetic drugs accompanied by a cell cycle delay caused by accumulation of cells at G1. 46 We exam-BCL11B, a novel putative oncogene in AML haematologica | 2014; 99 (5)ined the consequences of Bcl11b overexpression on proliferation and differentiation in a mouse myeloid 32D(GCSF-R) cell line model. The 32D(GCSF-R) cells, expressing fulllength murine Bcl11b cDNA, had a consistently decreased proliferation rate compared to cells expressing the empty vector or to the parental untransfected cells.…”