Characterization of the TCL-1 transgenic mouse as a preclinical drug development tool for human chronic lymphocytic leukemia

Johnson, Amy J.; Lucas, David M.; Muthusamy, Natarajan; Smith, Lisa L.; Edwards, Ryan B.; Lay, Michael De; Croce, Carlo M.; Grever, Michael R.; Byrd, John C.

doi:10.1182/blood-2005-12-011213

Cited by 118 publications

(115 citation statements)

References 29 publications

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“…24 In contrast, in actinomycin D-treated mice, no resistance development could be observed. The remaining three mice of the actinomycin D group lived until day 295, 338 and 388, nearly reaching their natural life span.…”

Section: Identification Of P53-independent Apoptosis Inducersmentioning

confidence: 95%

“…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%

“…Fludarabine was applied in cycles of 34 mg/kg for 5 days, i.p., a dose that has been described to prolong overall survival in TCL1 mice. 24 Mice were split into three groups of comparable mean tumor load and treated with one cycle either actinomycin D (0.06 mg/kg/14 days i.p., n ¼ 9), fludarabine (34 mg/kg/5 days i.p., n ¼ 6) or phosphate-buffered saline (14 days i.p., n ¼ 6). The median overall survival from time of engraftment was 49 days for the control, 80 days for fludarabine and 135 days for actinomycin D, revealing a strong life-prolonging effect of actinomycin D and, to a lesser degree, of fludarabine (log-rank test; Po0.001 for actinomycin D and P ¼ 0.007 for fludarabine, respectively).…”

Section: Identification Of P53-independent Apoptosis Inducersmentioning

confidence: 99%

“…Furthermore, the efficacy of actinomycin D is tested in two different mouse models for high-risk CLL. [22][23][24][25] …”

Section: Introductionmentioning

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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Section: Identification Of P53-independent Apoptosis Inducersmentioning

confidence: 95%

Section: Identification Of P53-independent Apoptosis Inducersmentioning

confidence: 99%

Section: Identification Of P53-independent Apoptosis Inducersmentioning

confidence: 99%

Section: Identification Of P53-independent Apoptosis Inducersmentioning

confidence: 99%

“…Furthermore, the efficacy of actinomycin D is tested in two different mouse models for high-risk CLL. [22][23][24][25] …”

Section: Introductionmentioning

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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Animal models for chronic lymphocytic leukemia

Pekarsky

Zanesi

Aqeilan

et al. 2006

J of Cellular Biochemistry

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B-cell chronic lymphocytic leukemia (B-CLL), the most common leukemia in the Western world, results from an expansion of a rare population of CD5+ mature B-lymphocytes. Although clinical features and genomic abnormalities in B-CLL have been studied in considerable detail, the molecular mechanisms underlying disease development has remained unclear until recently. In the last 4 years, several transgenic mouse models for B-CLL were generated. Investigations of these mouse models revealed that deregulation of three pathways, Tcl1-Akt pathway, TNF-NF-kB pathway, and Bcl2-mediated anti-apoptotic pathway, result in the development of B-CLL. While deregulation of TCL1 alone caused a B-CLL phenotype in mice, overexpression of Bcl2 required aberrantly activated TNF-NF-kB pathway signaling to yield the disease phenotype. In this article, we present what has been learned from mice with B-CLL phenotype and how these mouse models of B-CLL were used to test therapeutic treatments for this common leukemia.

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Mouse Models of Human Blood Cancers

Li¹

2008

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Characterization of the TCL-1 transgenic mouse as a preclinical drug development tool for human chronic lymphocytic leukemia

Cited by 118 publications

References 29 publications

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

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

Animal models for chronic lymphocytic leukemia

Mouse Models of Human Blood Cancers

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