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13q14 deletions in CLL involve cooperating tumor suppressors

Palamarchuk, Alexey ; Efanov, Alexey ; Nazaryan, Natalya ; [et al.]

American Society of Hematology ; 2010

In: Blood Vol. 115, No. 19 ( 2010-05-13), p. 3916-3922

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In: Blood, American Society of Hematology, Vol. 115, No. 19 ( 2010-05-13), p. 3916-3922

Abstract: 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-κB (NF-κB) pathway in CLL. To examine the possible role of DLEU7 in CLL, we investigated the effect of DLEU7 expression on NF-κB and nuclear factor of activated T cells (NFAT) activity. We found that DLEU7 functions as a potent NF-κB and NFAT inhibitor by physically interacting and inhibiting TACI and BCMA, members of the tumor necrosis factor (TNF) receptor family involved in B-CLL. In addition, DLEU7 expression in A549 lung cancer cells resulted in a decrease in S phase and increased apoptosis. The results suggest that loss of DLEU7 may cooperate with the loss of miR-15/16 in the pathogenesis of CLL.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2009-10-249367

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XA 33000

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XA 10000

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

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Tcl1 Expression in Chronic Lymphocytic Leukemia Is Regulated by miR-29 and miR-181

Pekarsky, Yuri ; Santanam, Urmila ; Cimmino, Amelia ; [et al.]

American Association for Cancer Research (AACR) ; 2006

In: Cancer Research Vol. 66, No. 24 ( 2006-12-15), p. 11590-11593

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In: Cancer Research, American Association for Cancer Research (AACR), Vol. 66, No. 24 ( 2006-12-15), p. 11590-11593

Abstract: B-cell chronic lymphocytic leukemia (B-CLL) is the most common human leukemia in the world. Deregulation of the TCL1 oncogene is a causal event in the pathogenesis of the aggressive form of this disease as was verified by using animal models. To study the mechanism of Tcl1 regulation in CLL, we carried out microRNA expression profiling of three types of CLL: indolent CLL, aggressive CLL, and aggressive CLL showing 11q deletion. We identified distinct microRNA signatures corresponding to each group of CLL. We further determined that Tcl1 expression is regulated by miR-29 and miR-181, two microRNAs differentially expressed in CLL. Expression levels of miR-29 and miR-181 generally inversely correlated with Tcl1 expression in the CLL samples we examined. Our results suggest that Tcl1 expression in CLL is, at least in part, regulated by miR-29 and miR-181 and that these microRNAs may be candidates for therapeutic agents in CLLs overexpressing Tcl1. (Cancer Res 2006; 66(24): 11590-3)

Type of Medium: Online Resource

ISSN: 0008-5472 , 1538-7445

URL: Article

DOI: 10.1158/0008-5472.CAN-06-3613

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Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2006

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Abstract LB-352: B-CLL phenotype in Eµ-miR-29 transgenic mice

Santanam, Urmila ; Zanesi, Nicola ; Efanov, Alexey ; [et al.]

American Association for Cancer Research (AACR) ; 2010

In: Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. LB-352-LB-352

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In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. LB-352-LB-352

Abstract: B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in the western world. Human B-CLL occurs in two forms: aggressive (showing high ZAP-70 expression and unmutated IgH VH) and indolent (showing low ZAP-70 expression and mutated IgH VH). We found that miR-29a is upregulated in indolent human B-CLL compared to aggressive B-CLL and normal CD19+ B-cells. To study the role of miR-29 in B-CLL, we generated Eµ-miR-29 transgenic mice overexpressing miR-29 in mouse B-cells. Flow cytometric analysis revealed a markedly expanded CD5+ population in the spleen of these mice starting at 2 months of age. Over 80% of miR-29 transgenic mice exhibited an expanded population of CD5+ B-cells, a characteristic of the B-CLL phenotype. An average of 56% of the B-cell population in these transgenics were CD5 positive. At the age of 2 years these mice showed significantly enlarged spleens and an increase in CD5+ B-cell population of up to 100% of B-cells. Over 8% (3/36) of Eµ-miR-29 transgenic mice developed frank leukemia and prematurely died from the disease at the age of 24-26 months. The expanded CD5+ B-cell population was found to be proliferative, with an increased number of cells in the S-phase of the cell cycle, compared to wild type CD19+ B-cells. These results suggest that deregulation of miR-29 can cause, or at least significantly contribute to the pathogenesis of indolent 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 LB-352.

Type of Medium: Online Resource

ISSN: 0008-5472 , 1538-7445

URL: Article

DOI: 10.1158/1538-7445.AM10-LB-352

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XA 10000

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2010

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Chronic lymphocytic leukemia modeled in mouse by targeted miR-29 expression

Santanam, Urmila ; Zanesi, Nicola ; Efanov, Alexey ; [et al.]

Proceedings of the National Academy of Sciences ; 2010

In: Proceedings of the National Academy of Sciences Vol. 107, No. 27 ( 2010-07-06), p. 12210-12215

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In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 27 ( 2010-07-06), p. 12210-12215

Abstract: B-cell chronic lymphocytic leukemia (B-CLL), the most common leukemia in the Western world, occurs in two forms, aggressive (showing for the most part high ZAP-70 expression and unmutated IgH V H ) and indolent (showing low ZAP-70 expression and mutated IgH V H ). We found that miR-29a is up-regulated in indolent human B-CLL as compared with aggressive B-CLL and normal CD19 + B cells. To study the role of miR-29 in B-CLL, we generated Eμ- miR-29 transgenic mice overexpressing miR-29 in mouse B cells. Flow cytometric analysis revealed a markedly expanded CD5 + population in the spleen of these mice starting at 2 mo of age, with 85% (34/40) of miR-29 transgenic mice exhibiting expanded CD5 + B-cell populations, a characteristic of B-CLL. On average, 50% of B cells in these transgenic mice were CD5 positive. At 2 y of age the mice showed significantly enlarged spleens and an increase in the CD5 + B-cell population to ∼100%. Of 20 Eμ- miR-29 transgenic mice followed to 24–26 mo of age, 4 (20%) developed frank leukemia and died of the disease. These results suggest that dysregulation of miR-29 can contribute to the pathogenesis of indolent B-CLL.

Type of Medium: Online Resource

ISSN: 0027-8424 , 1091-6490

URL: Article

DOI: 10.1073/pnas.1007186107

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TA 1000

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WA 15000

Language: English

Publisher: Proceedings of the National Academy of Sciences

Publication Date: 2010

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Tcl1 interacts with Atm and enhances NF-κB activation in hematologic malignancies

Gaudio, Eugenio ; Spizzo, Riccardo ; Paduano, Francesco ; [et al.]

American Society of Hematology ; 2012

In: Blood Vol. 119, No. 1 ( 2012-01-05), p. 180-187

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In: Blood, American Society of Hematology, Vol. 119, No. 1 ( 2012-01-05), p. 180-187

Abstract: The T-cell leukemia/lymphoma 1 (TCL1) oncogene is a target of chromosomal translocations and inversions at 14q31.2, and its rearrangement in T cells causes T-cell prolymphocytic leukemias. TCL1 dysregulation in B cells is responsible for the development of an aggressive form of chronic lymphocytic leukemia (CLL), the most common human leukemia. We have investigated the mechanisms underlying the oncogenic functions of Tcl1 protein using a mass spectrometry approach and have identified Atm (ataxia-telangiectasia mutated) as a candidate Tcl1-interacting protein. The Tcl1-Atm complex formation was validated by coimmunoprecipitation experiments. Importantly, we show that the association of Atm with Tcl1 leads to enhanced IκBα phosphorylation and ubiquitination and subsequent activation of the NF-κB pathway. Our findings reveal functional cross-talk between Atm and Tcl1 and provide evidence for a novel pathway that could be targeted in leukemias and lymphomas.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2011-08-374561

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XA 33000

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Language: English

Publisher: American Society of Hematology

Publication Date: 2012

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Akt Phosphorylates and Regulates Pdcd4 Tumor Suppressor Protein

Palamarchuk, Alexey ; Efanov, Alexey ; Maximov, Vadim ; [et al.]

American Association for Cancer Research (AACR) ; 2005

In: Cancer Research Vol. 65, No. 24 ( 2005-12-15), p. 11282-11286

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In: Cancer Research, American Association for Cancer Research (AACR), Vol. 65, No. 24 ( 2005-12-15), p. 11282-11286

Abstract: Programmed cell death 4 (Pdcd4) is a tumor suppressor protein that interacts with eukaryotic initiation factor 4A and inhibits protein synthesis. Pdcd4 also suppresses the transactivation of activator protein-1 (AP-1)–responsive promoters by c-Jun. The Akt (protein kinase B) serine/threonine kinase is a key mediator of phosphoinositide 3-kinase pathway involved in the regulation of cell proliferation, survival, and growth. Because Pdcd4 has two putative Akt phosphorylation sites at Ser67 and Ser457, we investigated whether Akt phosphorylates and regulates Pdcd4. Our results show that Akt specifically phosphorylates Ser67 and Ser457 residues of Pdcd4 in vitro and in vivo. We further show that phosphorylation of Pdcd4 by Akt causes nuclear translocation of Pdcd4. Using luciferase assay, we show that phosphorylation of Pdcd4 by Akt also causes a significant decrease of the ability of Pdcd4 to interfere with the transactivation of AP-1–responsive promoter by c-Jun. (Cancer Res 2005; 65(24): 11282-6)

Type of Medium: Online Resource

ISSN: 0008-5472 , 1538-7445

URL: Article

DOI: 10.1158/0008-5472.CAN-05-3469

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Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2005

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Abstract 401: CD5+CD23+ leukemic cell populations in Tcl1 transgenic mice show significantly increased proliferation and Akt phosphorylation

Efanov, Alexey A. ; Zanesi, Nicola ; Maximov, Vadim ; [et al.]

American Association for Cancer Research (AACR) ; 2010

In: Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 401-401

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In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 401-401

Abstract: 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.

Type of Medium: Online Resource

ISSN: 0008-5472 , 1538-7445

URL: Article

DOI: 10.1158/1538-7445.AM10-401

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Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2010

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Akt Phosphorylates Tal1 Oncoprotein and Inhibits Its Repressor Activity

Palamarchuk, Alexey ; Efanov, Alexey ; Maximov, Vadim ; [et al.]

American Association for Cancer Research (AACR) ; 2005

In: Cancer Research Vol. 65, No. 11 ( 2005-06-01), p. 4515-4519

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In: Cancer Research, American Association for Cancer Research (AACR), Vol. 65, No. 11 ( 2005-06-01), p. 4515-4519

Abstract: The helix-loop-helix transcription factor Tal1 is required for blood cell development and its activation is a frequent event in T-cell acute lymphoblastic leukemia. The Akt (protein kinase B) kinase is a key player in transduction of antiapoptotic and proliferative signals in T cells. Because Tal1 has a putative Akt phosphorylation site at Thr90, we investigated whether Akt regulates Tal1. Our results show that Akt specifically phosphorylates Thr90 of the Tal1 protein within its transactivation domain in vitro and in vivo. Coimmunoprecipitation experiments showed the presence of Tal1 in Akt immune complexes, suggesting that Tal1 and Akt physically interact. We further showed that phosphorylation of Tal1 by Akt causes redistribution of Tal1 within the nucleus. Using luciferase assay, we showed that phosphorylation of Tal1 by Akt decreased repressor activity of Tal1 on EpB42 (P4.2) promoter. Thus, these data indicate that Akt interacts with Tal1 and regulates Tal1 by phosphorylation at Thr90 in a phosphatidylinositol 3-kinase–dependent manner.

Type of Medium: Online Resource

ISSN: 0008-5472 , 1538-7445

URL: Article

DOI: 10.1158/0008-5472.CAN-05-0751

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Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2005

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Tal1 Transgenic Expression Reveals Absence of B Lymphocytes

Palamarchuk, Alexey ; Zanesi, Nicola ; Aqeilan, Rami I. ; [et al.]

American Association for Cancer Research (AACR) ; 2006

In: Cancer Research Vol. 66, No. 12 ( 2006-06-15), p. 6014-6017

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In: Cancer Research, American Association for Cancer Research (AACR), Vol. 66, No. 12 ( 2006-06-15), p. 6014-6017

Abstract: TAL1 oncogene encodes a helix-loop-helix transcription factor, Tal1, which is required for blood cell development, and its activation is a frequent event in T-cell acute lymphoblastic leukemia. Tal1 interacts and inhibits other helix-loop-helix factors such as E47 and HEB. To investigate the function of Tal1 in B cells, we generated Eμ-TAL1 transgenic mouse line, expressing Tal1 in mouse B-cell lineage. Fluorescence-activated cell sorting (FACS) analysis of lymphocytes isolated from spleens of five out of five founders reveals complete absence of IgM- or CD19-expressing cells. Only 2% to 3% of these cells were B220+ and 100% of B220+ cells were CD43+, indicating that these mice were able to make pro-B cells. Similarly, FACS analysis of bone marrow cells in Eμ-TAL1 mice revealed complete absence of B220+IgM+ and B220+CD19+ cells. Analysis of the recombination status of IgH genes revealed the presence of D-J but absence or drastic reduction of V-D-J rearrangements. Our results suggest that Tal1 overexpression in B cells results in a phenotype similar to that of B cells of E47/E2A knockout animals. This represents first in vivo evidence that Tal1 can completely inhibit E47/E2A function. (Cancer Res 2006; 66(12): 6014-7)

Type of Medium: Online Resource

ISSN: 0008-5472 , 1538-7445

URL: Article

DOI: 10.1158/0008-5472.CAN-06-0937

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Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2006

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Tcl1 functions as a transcriptional regulator and is directly involved in the pathogenesis of CLL

Pekarsky, Yuri ; Palamarchuk, Alexey ; Maximov, Vadim ; [et al.]

Proceedings of the National Academy of Sciences ; 2008

In: Proceedings of the National Academy of Sciences Vol. 105, No. 50 ( 2008-12-16), p. 19643-19648

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In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 105, No. 50 ( 2008-12-16), p. 19643-19648

Abstract: 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. To examine the mechanisms by which Tcl1 protein exerts oncogenic activity in B cells, we investigated the effect of Tcl1 expression on NF-κB and activator protein 1 (AP-1) activity. We found that Tcl1 physically interacts with c-Jun, JunB, and c-Fos and inhibits AP-1 transcriptional activity. Additionally, Tcl1 activates NF-κB by physically interacting with p300/CREB binding protein. We then sequenced the TCL1 gene in 600 B-CLL samples and found 2 heterozygous mutations: T38I and R52H. Importantly, both mutants showed gain of function as AP-1 inhibitors. The results indicate that Tcl1 overexpression causes B-CLL by directly enhancing NF-κB activity and inhibiting AP-1.

Type of Medium: Online Resource

ISSN: 0027-8424 , 1091-6490

URL: Article

DOI: 10.1073/pnas.0810965105

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Language: English

Publisher: Proceedings of the National Academy of Sciences

Publication Date: 2008

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