Effect of Rapamycin on Mouse Chronic Lymphocytic Leukemia and the Development of Nonhematopoietic Malignancies in <i>Eμ-TCL1</i> Transgenic Mice

Zanesi, Nicola; Aqeilan, Rami I.; Drusco, Alessandra; Kaou, Mohamed; Sevignani, Cinzia; Costinean, Stefan; Bortesi, Laura; Rocca, Gaspare La; Koldovský, P.; Volinia, Stefano; Mancini, Rita; Calin, George A.; Scott, Charles P.; Pekarsky, Yuri; Croce, Carlo M.

doi:10.1158/0008-5472.can-05-3426

Cited by 64 publications

(66 citation statements)

References 23 publications

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“…1C), with an Ϸ5-fold increase at 24 h. dbcAMP treatment of Jurkat T cells, which do not express TCL1, failed to induce TCL1 (data not shown), likely because dbcAMP cannot overcome epigenetic silencing at the TCL1 locus (22). In contrast, Bchronic lymphohocytic leukemia (B-CLL) cells likely require TCL1 for survival (12,14,29,30), and the Ϫ424luc reporter was activated by dbcAMP in at least two of three patient samples between 14-and 140-fold over untreated levels (Fig. 1D).…”

Section: Resultsmentioning

confidence: 99%

TORC2 regulates germinal center repression of the TCL1 oncoprotein to promote B cell development and inhibit transformation

Kuraishy

French

Sherman

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Aberrant expression of the TCL1 oncoprotein promotes malignant transformation of germinal center (GC) B cells. Repression of TCL1in GC B cells facilitates FAS-mediated apoptosis and prevents lymphoma formation. However, the mechanism for this repression is unknown. Here we show that the CREB coactivator TORC2 directly regulates TCL1 expression independent of CREB Ser-133 phosphorylation and CBP/p300 recruitment. GC signaling through CD40 or the BCR, which activates pCREB-dependent genes, caused TORC2 phosphorylation, cytosolic emigration, and TCL1 repression. Signaling via cAMP-inducible pathways inhibited TCL1 repression and reduced apoptosis, consistent with a prosurvival role for TCL1 before GC selection and supporting an initiating role for aberrant TCL1 expression during GC lymphomagenesis. Our data indicate that a novel CREB/TORC2 regulatory mode controls the normal program of GC gene activation and repression that promotes B cell development and circumvents oncogenic progression. Our results also reconcile a paradox in which signals that activate pCREB/CBP/ p300 genes concurrently repress TCL1 to initiate its silencing.gene regulation ͉ lymphomagenesis ͉ signal transduction T he germinal center (GC) is home to T cell-dependent antigen-driven B cell maturation, memory B and plasma cell production, and the site of origin for most human B cell lymphomas (1-3). GC B cells undergo critical changes in gene expression that are required for proper development and protection from oncogenesis (4, 5). The generation of an appropriate humoral response is insured by negative selection, primarily mediated by FAS-induced apoptosis (6-8). Escape from apoptosis results in autoimmunity and B cell transformation (8).TCL1 functions as a coactivator of the cell survival kinase AKT (9, 10). In mature T cell tumors, TCL1 expression is aberrantly elevated by rearrangements into T cell receptor loci (11). Physiologic TCL1 expression is largely limited to B lineage cells and is robust from pre-B cells through peripheral naïve B cells, followed by a critical 40-60% repression in GC B cells and complete silencing in post-GC memory B and plasma cells (12,13). Most B cell lymphomas that arise by transformation of GC-experienced B cells exhibit elevated TCL1 expression by escape from GC mechanism(s) of TCL1 repression (12,14,15). Interestingly, transgenic mice with TCL1 expression levels stabilized in GC lymphocytes develop cancers that resemble a spectrum of human GC B cell lymphomas (16).Unrepressed TCL1 expression inhibits FAS-induced B cell apoptosis independent of activation by BCR survival signaling (17, 18). Impaired apoptosis from failed TCL1 repression in GC B cells connects TCL1 dysregulation in patient lymphomas (12, 14) to a mechanism for increased transformation (16,18). Factors so far suggested to regulate TCL1, including Nur77 (19,20), miRNA-29 and miRNA-181 (21), Sp1 (22), and EBV infection (23), fail to adequately explain TCL1 repression in GC B cells and its continued aberrant expression in lymphomas (11).Its role in ...

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Section: Resultsmentioning

confidence: 99%

TORC2 regulates germinal center repression of the TCL1 oncoprotein to promote B cell development and inhibit transformation

Kuraishy

French

Sherman

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…In vivo experiments were performed in C57BL/6 wild-type mice, which were engrafted with tumor cells from Em-TCL-1 transgenic mice as described earlier. 22,30 The percentage of CD5 þ /CD19 þ cells in the peripheral blood was routinely checked in mice by taking blood from the tail vein and analyzing it via flow cytometry. When the percentage of tumor cells in the peripheral blood reached 40-60%, treatment was started.…”

Section: Cll Mouse Modelmentioning

confidence: 99%

“…22 The TCL1 mouse was constructed to specifically overexpress the TCL1 gene in B cells using the Em-enhancer promoter system. [22][23][24]30 The mean difference between the expressed Ig V(H) genes of these mice and germ line is only 0.5%, thus the TCL1 mouse is thought to model the more aggressive, IgV(H) unmutated form of the disease in humans. 37 Lymphocytes of TCL1-mice with overt leukemia were engrafted in 10 C57BL/6 mice, as previously described.…”

Section: Identification Of P53-independent Apoptosis Inducersmentioning

confidence: 99%

“…37 Lymphocytes of TCL1-mice with overt leukemia were engrafted in 10 C57BL/6 mice, as previously described. [22][23][24]30 However, two of them died before the start of treatment, indicating that they had advanced tumor progression. The remaining eight mice were equally divided between control (phosphate-buffered saline) and treatment arms (0.06 mg/kg actinomycin D for 14 consecutive days i.p.).…”

Section: Identification Of P53-independent Apoptosis Inducersmentioning

confidence: 99%

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Actinomycin D induces p53-independent cell death and prolongs survival in high-risk chronic lymphocytic leukemia

et al. 2012

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Chronic lymphocytic leukemia (CLL) is the most prevalent lymphoid malignancy in the elderly of the Western world. Although treatment options have improved over the past two decades, 10-15% of patients still have a poor prognosis and are often resistant to therapy. Aberrations in the p53 pathway, such as a deleted (del17p13) or mutated p53 gene, are highly enriched in this class of patients. In an extensive screen for p53-independent apoptosis inducers, actinomycin D was identified from 1496 substances and shown to induce apoptosis in primary CLL cells derived from high-risk patients including those with aberrant p53, revealing a novel p53-independent mechanism of action. Both pro-survival genes BCL2 and MCL1 are targeted by actinomycin D, in contrast to fludarabine the backbone of current treatment schedules. In the well-established TCL1 transgenic mouse model for high-risk CLL, actinomycin D treatment was more effective in reducing tumor load than fludarabine, with no evidence of resistance after three treatment cycles and an overall survival increase of over 300%. Tumor load reduction was coupled to BCL2 downregulation. Our results identify the clinically approved compound actinomycin D as a potentially valuable treatment option for CLL high-risk patients.

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“…Moreover, TCL1 has been shown to be constitutively expressed in a tightly regulated manner in lymphoid cells of B and T origins (Narducci et al, 1997a, b;Takizawa et al, 1998;Teitell et al, 1999;Kang et al, 2005). Functionally, Tcl1 exerts its function by binding the pleckstrin domain of AKT proteins, thereafter increasing AKT kinase activity and enhancing AKT nuclear translocation in vitro (Laine et al, 2000;Pekarsky et al, 2000;Kunstle et al, 2002) and in vivo (Zanesi et al, 2006). In particular, the presence of Tcl1 allows the serine-473 transphosphorylation of AKT proteins in the oligomeric complex, thus ensuring maximal kinase activity and facilitating an amplification loop of the antiapoptotic, proliferative stimuli controlled by the PI3-kinase-AKT pathway .…”

Section: Introductionmentioning

confidence: 99%

The Tcl1 oncogene defines secondary hair germ cells differentiation at catagen–telogen transition and affects stem-cell marker CD34 expression

et al. 2009

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Overexpression of the TCL1 gene family plays a role in the onset of T-cell leukemias in mice and in humans. The Tcl1 gene is tightly regulated during early embryogenesis in which it participates in embryonic stem (ES)-cells proliferation and during lymphoid differentiation. Here, we provide evidences that Tcl1 is also important in mouse hair follicle (HF) and skin homeostasis. We found that Tcl1 À/À adult mice exhibit hair loss, leading to alopecia with extensive skin lesions. By analysing Tcl1 expression in the wild-type (wt) skin through different stages of hair differentiation, we observe high levels in the secondary hair germ (HG) cells and hair bulges, during early anagen and catagen-telogen transition phases. The loss of Tcl1 does not result in apparent skin morphological defects during embryonic development and at birth, but its absence causes a reduction of proliferation in anagen HFs. Importantly, we show the that absence of Tcl1 induces a significant loss of the stem-cell marker CD34 (but not a6-integrin) expression in the bulge cells, which is necessary to maintain stem-cell characteristics. Therefore, our findings indicate that Tcl1 gene(s) might have important roles in hair formation, by its involvement in cycling and self-renewal of transient amplifying (TA) and stem-cell (SC) populations.

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Effect of Rapamycin on Mouse Chronic Lymphocytic Leukemia and the Development of Nonhematopoietic Malignancies in Eμ-TCL1 Transgenic Mice

Cited by 64 publications

References 23 publications

TORC2 regulates germinal center repression of the TCL1 oncoprotein to promote B cell development and inhibit transformation

TORC2 regulates germinal center repression of the TCL1 oncoprotein to promote B cell development and inhibit transformation

Actinomycin D induces p53-independent cell death and prolongs survival in high-risk chronic lymphocytic leukemia

The Tcl1 oncogene defines secondary hair germ cells differentiation at catagen–telogen transition and affects stem-cell marker CD34 expression

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