Analysis of the expression pattern of the BCL11B gene and its relatives in patients with T-cell acute lymphoblastic leukemia

<p>Abstract</p> <p>Background</p> <p>In a human T-cell acute lymphoblastic leukemia (T-ALL) cell line (Molt-4), siRNA-mediated suppression of <it>BCL11B </it>expression was shown to inhibit proliferation and induce apoptosis, functions which may be related to genes involved in apoptosis (such as <it>TNFSF10 </it>and <it>BCL2L1</it>) and TGF-β pathways (such as <it>SPP1</it>and <it>CREBBP</it>).</p> <p>Methods</p> <p>The expression levels of the above mentioned genes and their correlation with the <it>BCL11B </it>gene were analyzed in patients with T-ALL using the TaqMan and SYBR Green I real-time polymerase chain reaction technique.</p> <p>Results</p> <p>Expression levels of <it>BCL11B, BCL2L1</it>, and <it>CREBBP </it>mRNA in T-ALL patients were significantly higher than those from healthy controls (<it>P <</it>0.05). In T-ALL patients, the <it>BCL11B </it>expression level was negatively correlated with the <it>BCL2L1 </it>expression level (<it>r</it>_s= -0.700; <it>P </it><it><</it>0.05), and positively correlated with the <it>SPP1 </it>expression level (<it>r</it>_s= 0.683; <it>P </it><it><</it>0.05). In healthy controls, the <it>BCL11B </it>expression level did not correlate with the <it>TNFSF10</it>, <it>BCL2L1</it>, <it>SPP1</it>, or <it>CREBBP </it>expression levels.</p> <p>Conclusions</p> <p>Over-expression of <it>BCL11B </it>might play a role in anti-apoptosis in T-ALL cells through up-regulation of its downstream genes <it>BCL2L1 </it>and <it>CREBBP</it>.</p

Expression and distribution of PPP2R5C gene in leukemia

<p>Abstract</p> <p>Background</p> <p>Recently, we clarified at the molecular level novel chromosomal translocation t(14;14)(q11;q32) in a case of Sézary syndrome, which caused a rearrangement from TRAJ7 to the <it>PPP2R5C </it>gene. <it>PPP2R5C </it>is one of the regulatory B subunits of protein phosphatase 2A (PP2A). It plays a crucial role in cell proliferation, differentiation, and transformation. To characterize the expression and distribution of five different transcript variants of the <it>PPP2R5C </it>gene in leukemia, we analyzed the expression level of <it>PPP2R5C </it>in peripheral blood mononuclear cells from 77 patients with <it>de novo </it>leukemia, 26 patients with leukemia in complete remission (CR), and 20 healthy individuals by real-time PCR and identified the different variants of <it>PPP2R5C </it>by RT-PCR.</p> <p>Findings</p> <p>Significantly higher expression of <it>PPP2R5C </it>was found in AML, CML, T-ALL, and B-CLL groups in comparison with healthy controls. High expression of <it>PPP2R5C </it>was detected in the B-ALL group; however, no significant difference was found compared with the healthy group. The expression level of <it>PPP2R5C </it>in the CML-CR group decreased significantly compared with that in the <it>de novo </it>CML group and was not significantly different from the level in the healthy group. By using different primer pairs that covered different exons, five transcript variants of <it>PPP2R5C </it>could be identified. All variants could be detected in healthy samples as well as in all the leukemia samples, and similar frequencies and distributions of <it>PPP2R5C </it>were indicated.</p> <p>Conclusions</p> <p>Overexpression of <it>PPP2R5C </it>in T-cell malignancy as well as in myeloid leukemia cells might relate to its proliferation and differentiation. Investigation of the effect of target inhibition of this gene might be beneficial to further characterization of molecular mechanisms and targeted therapy in leukemia.</p

Decreased level of recent thymic emigrants in CD4+ and CD8+T cells from CML patients

<p>Abstract</p> <p>Background</p> <p>T-cell immunodeficiency is a common feature in cancer patients, which may relate to initiation and development of tumor. Based on our previous finding, to further characterize the immune status, T cell proliferative history was analyzed in CD4+ and CD8+ T cells from chronic myeloid leukemia (CML) patients.</p> <p>Methods</p> <p>Quantitative analysis of δRec-ψJα signal joint T cell receptor excision circles (sjTRECs) was performed in PBMCs, CD3+, CD4+ and CD8+T cells by real-time PCR, and the analysis of 23 <it>TRBV-D1 </it>sjTRECs was performed by semi-nested PCR. Forty eight CML cases in chronic phase (CML-CP) were selected for this study and 17 healthy individuals served as controls.</p> <p>Results</p> <p>The levels of δRec-ψJα sjTRECs in PBMCs, CD3+, CD4+, and CD8+ T cells were significantly decreased in CML patients, compared with control groups. Moreover, the numbers of detectable <it>TRBV </it>subfamily sjTRECs, as well as the frequency of particular <it>TRBV-BD</it>1 sjTRECs in patients with CML were significantly lower than those from healthy individuals.</p> <p>Conclusions</p> <p>We observed decreased levels of recent thymic emigrants in CD4+ and CD8+ T cells that may underlay the persistent immunodeficiency in CML patients.</p

Genome-wide analyses identify KLF4 as an important negative regulator in T-cell acute lymphoblastic leukemia through directly inhibiting T-cell associated genes

é 2015 Li et al. Background: Kruppel-like factor 4 (KLF4) induces tumorigenesis or suppresses tumor growth in a tissue-dependent manner. However, the roles of KLF4 in hematological malignancies and the mechanisms of action are not fully understood. Methods: Inducible KLF4-overexpression Jurkat cell line combined with mouse models bearing cell-derived xenografts and primary T-cell acute lymphoblastic leukemia (T-ALL) cells from four patients were used to assess the functional role of KLF4 in T-ALL cells in vitro and in vivo. A genome-wide RNA-seq analysis was conducted to identify genes regulated by KLF4 in T-ALL cells. Chromatin immunoprecipitation (ChIP) PCR was used to determine direct binding sites of KLF4 in T-ALL cells. Results: Here we reveal that KLF4 induced apoptosis through the BCL2/BCLXL pathway in human T-ALL cell lines and primary T-ALL specimens. In consistence, mice engrafted with KLF4-overexpressing T-ALL cells exhibited prolonged survival. Interestingly, the KLF4-induced apoptosis in T-ALL cells was compromised in xenografts but the invasion capacity of KLF4-expressing T-ALL cells to hosts was dramatically dampened. We found that KLF4 overexpression inhibited T cell-associated genes including NOTCH1, BCL11B, GATA3, and TCF7. Further mechanistic studies revealed that KLF4 directly bound to the promoters of NOTCH1, BCL2, and CXCR4 and suppressed their expression. Additionally, KLF4 induced SUMOylation and degradation of BCL11B. Conclusions: These results suggest that KLF4 as a major transcription factor that suppresses the expression of T-cell associated genes, thus inhibiting T-ALL progression.Link_to_subscribed_fulltex

Dynamic consistent NSFD scheme for a viral infection model with cellular infection and general nonlinear incidence

Abstract We study a discrete-time model with diffusion that describe the dynamics of viral infections by using nonstandard finite difference (NSFD) scheme. The original model we considered was a viral infection model with cellular infection and general nonlinear incidence. We analyze thoroughly the dynamical properties of both discrete and original continuous models and show that the discrete system is dynamically consistent with the original continuous model, including positivity and boundedness of solutions, equilibria, and their global properties. The results imply that the NSFD scheme can efficiently preserve the global dynamics properties of the corresponding continuous model. Some numerical simulations are carried out to validate the theoretical results

TIPE2 negatively regulates inflammation by switching arginine metabolism from nitric oxide synthase to arginase.

TIPE2, the tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 (TNFAIP8L2), plays an essential role in maintaining immune homeostasis. It is highly expressed in macrophages and negatively regulates inflammation through inhibiting Toll-like receptor signaling. In this paper, we utilized RAW264.7 cells stably transfected with a TIPE2 expression plasmid, as well as TIPE2-deficient macrophages to study the roles of TIPE2 in LPS-induced nitric oxide (NO) and urea production. The results showed that TIPE2-deficiency significantly upregulated the levels of iNOS expression and NO production in LPS-stimulated macrophages, but decreased mRNA levels of arginase I and urea production. However, TIPE2 overexpression in macrophages was capable of downregulating protein levels of LPS-induced iNOS and NO, but generated greater levels of arginase I and urea production. Furthermore, TIPE2-/- mice had higher iNOS protein levels in lung and liver and higher plasma NO concentrations, but lower levels of liver arginase I compared to LPS-treated WT controls. Interestingly, significant increases in IκB degradation and phosphorylation of JNK, p38, and IκB were observed in TIPE2-deficient macrophages following LPS challenge. These results strongly suggest that TIPE2 plays an important role in shifting L-arginase metabolism from production of NO to urea, during host inflammatory response