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B-cell chronic lymphocytic leukemia (CLL) is the most common human leukemia. 13q14 deletions are most common chromosomal alterations in CLL. We previously reported that miR-15/16 is a target of 13q14 deletions and plays a tumor suppressor role by targeting BCL2. Because DLEU7 is located near miR-15/16 and is also positioned within a minimal deleted region, we investigated whether DLEU7 could also play a tumor suppressor role. Recent studies of transgenic mouse models demonstrated the importance of the nuclear factor-B (NF-B) pathway in CLL. To examine the possible role of DLEU7 in CLL, we investigated the effect of DLEU7 expression on NF-B and nuclear factor of activated T cells (NFAT) activity. We found that DLEU7 functions as a potent NF-B and NFAT inhibitor by physically interacting and inhibiting TACI and IntroductionChronic lymphocytic leukemia (CLL) lymphocytes have mature appearance and the B220 ϩ CD5 ϩ phenotype. 1,2 Several chromosomal aberrations occur frequently in CLL cases, including 13q deletions (ϳ 50%), 11q23 deletions (18%), trisomy 12 (12%), and 17p deletions (7%). 3 The 13q14 deletion is the most common B-CLL aberration and is seen by cytogenetics in approximately half of the cases. 3 13q14 is seen predominantly in the indolent form of CLL and is associated with low levels of ZAP70 expression and mutated variable region genes of immunoglobulins. 4 Analysis of an approximately 30-kb deletion at 13q14.3 and chromosomal breakpoint mapping of translocation t(2:13)(q32;q14) led to the discovery of 2 physically linked microRNAs, miR-15a and miR-16-1, as targets of these deletions. 5 Furthermore, both, miR-15a and miR-16-1 were reduced in expression in most CLL cases, 5 and further studies indicated that miR-15a/miR-16-1 negatively regulate Bcl2 expression. 6 These findings indicated that down-regulation of miR-15/16 and subsequent Bcl2 up-regulation contribute to CLL pathogenesis. 5 A high-resolution map of 13q14 deletions using 171 CLL samples was recently reported. 7 These data indicated that the minimal deleted region, in addition to miR-15/16, also contains the DLEU7 gene ( Figure 1A). 7 DLEU7 was previously identified as a candidate tumor suppressor gene at 13q14. 8 It encodes a 221-amino acid protein with no homology to known proteins. No mutations in DLEU7 were found in 45 CLL samples, although the DLEU7 promoter was methylated in 61% of CLL. 8 Since DLEU7 is the only protein-coding gene located within the minimal deleted region at 13q14, we investigated whether DLEU7 can function as a tumor suppressor. Methods CLL samples and real-time PCR experimentsA total of 25 CLL samples were obtained after informed consent from patients diagnosed with CLL from the CLL Research Consortium. Research was performed with the approval of the Institutional Review Board of Ohio State University. Briefly, blood was obtained from patients with CLL, and lymphocytes were isolated through Ficoll/Hypaque gradient centrifugation (Amersham Biosciences) and processed for RNA extraction by using the standard TRIzol met...

Lung cancer is the leading cause of cancer mortality in the world today. Although some advances in lung cancer therapy have been made, patient survival is still poor. MicroRNAs (miRNAs) can act as oncogenes or tumor-suppressor genes in human malignancy. The miR-34 family consists of tumor-suppressive miRNAs, and its reduced expression has been reported in various cancers, including non-small cell lung cancer (NSCLC). In this study, we found that miR-34a and miR-34c target platelet-derived growth factor receptor alpha and beta (PDGFR-α and PDGFR-β), cell surface tyrosine kinase receptors that induce proliferation, migration and invasion in cancer. MiR-34a and miR-34c were downregulated in lung tumors compared to normal tissues. Moreover, we identified an inverse correlation between PDGFR-α/β and miR-34a/c expression in lung tumor samples. Finally, miR-34a/c overexpression or downregulation of PDGFR-α/β by siRNAs, strongly augmented the response to TNF-related apoptosis inducing ligand (TRAIL) while reducing migratory and invasive capacity of NSCLC cells.

B-cell chronic lymphocytic leukemia (CLL) is the most common human leukemia. Deregulation of the T-cell leukemia/lymphoma 1 oncogene (TCL1) in mouse B cells causes a CD5 + leukemia similar to aggressive human CLL. To examine the mechanisms by which Tcl1 protein exerts its oncogenic activity in B cells, we performed proteomics experiments to identify its interacting partners. We found that Tcl1 physically interacts with de novo DNA methylthansferases Dnmt3A and Dnmt3B. We further investigated the effects of Tcl1 up-regulation on the enzymatic activity of Dnmt3A and found that Tcl1 overexpression drastically inhibits Dnmt3A function. In addition, B cells from TCL1 transgenic mice showed a significant decrease in DNA methylation compared with WT controls. Similarly, CLL samples with high Tcl1 expression showed a decrease in DNA methylation compared with CLL samples with low Tcl1 expression. Given the previous reports of inactivating mutations of DNMT3A in acute myelogenous leukemia and myelodysplastic syndrome, our results suggest that inhibition of de novo DNA methylation may be a common oncogenic mechanism in leukemogenesis.T he lymphocytes of B-cell chronic lymphocytic leukemia (CLL) are mostly resting cells with mature appearance and the B220 + CD5 + phenotype (1, 2). The TCL1 oncogene has been identified as a target of chromosomal translocations and inversions at 14q31.2 in T-cell prolymphocytic leukemias (3). We previously showed that transgenic mice overexpressing TCL1 in B cells develop an aggressive form of CLL (4), and that aggressive human CLLs overexpress Tcl1 (5). These findings indicate that deregulation of TCL1 is critically important in the pathogenesis of the aggressive form of CLL. In previously work, we demonstrated that Tcl1 is a coactivator of the Akt oncoprotein (6). Akt could be robustly activated in mouse B cells by homozygous deletion of Pten (7). Surprisingly, these mice did not develop B-cell malignancies (7), suggesting that Tcl1 deregulation in B cells causes CLL by mechanisms other than Akt activation. We recently reported that Tcl1 functions as a transcriptional regulator and contributes to CLL pathogenesis by inhibiting activating protein 1 (AP-1) and activating NF-κB, and that that CLL-specific TCL1 mutants show gain of function in AP-1 inhibition (8).Three human genes-DNMT1, DNMT3A, and DNMT3B-encode DNA methyltransferases, enzymes responsible for methylation of CpG islands (9). Whereas DNMT1 functions mainly in maintaining methylation patterns, DNMT3A and DNMT3B encode de novo DNA methyltransferases (9). Inactivating mutations of DNMT3A have been reported in acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) (10-12). To further examine the mechanisms by which Tcl1 protein exerts oncogenic activity in B-cells, we used a proteomic approach to identify its interacting partners. This approach identified Dnmt3a and Dnmt3b as putative Tcl1 interactors.

B-cell chronic lymphocytic leukemia (B-CLL) is the most common adult leukemia. Deregulation of the T-cell leukemia/lymphoma 1 (TCL1) oncogene in mouse B cells causes a CD5-positive leukemia similar to aggressive human B-CLLs. We recently reported that levels of TCL1 expression in B-CLL are regulated by miR-29 and miR-181 that target 3′ UTR of TCL1. To determine whether treatment with microRNAs targeting TCL1 can inhibit B-CLL in mice, we generated TCL1 transgenic mice using a construct containing the 3′ and 5′ UTRs of TCL1 under B-cell-specific Eμ promoter (Eμ-TCL1FL). At the age of 16–20 months, these mice showed B-CLL-like disease. Immunophenotyping revealed accumulation of CD5 + CD23 + B220 + population in spleens and lymph nodes. Our results show that CD5 + CD23 + B-cell populations from Eμ-TCL1FL mice actively proliferate and show significantly increased levels of phospho-Akt. El-TCL1FL mice showed immunological abnormalities similar to human B-CLL, including hypoimmunoglobulinemia, abnormal levels of cytokines and impaired immune response. These findings revealed biochemical and immunological similarities between Tcl1-driven B-CLL in mice and human B-CLL.

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B-cell chronic lymphocytic leukemia (B-CLL) is the most common human leukemia. Deregulation of the T-cell leukemia/lymphoma 1 (TCL1) oncogene in mouse B-cells causes a CD5 positive leukemia similar to aggressive human B-CLLs. We recently reported that TCL1 expression in B-CLL is regulated by miR29 and miR181. To determine whether treatment with microRNAs can inhibit B-CLL in mice by targeting TCL1 we generated TCL1 transgenic mice using a construct containing 3’ and 5’ UTRs of TCL1 under B-cell specific Eμ promoter (Eμ-TCL1fl). At the age of 12-18 months these mice showed B-CLL like disease. Immunophenotyping revealed accumulation of CD5+CD23+B220+ population in spleens and lymph nodes. Our results show that CD5+CD23+ B-cell populations from Eμ-TCL1fl mice actively proliferate and display significantly increased levels of phospho-Akt. Eμ-TCL1fl mice showed immunological abnormalities similar to human B-CLL, including hypoimmunoglobulinemia, abnormal levels of cytokines, and impaired immune response. These findings revealed biochemical and immunological similarities between Tcl1 driven B-CLL in mice and human B-CLL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 401.