NOTCH1-induced T-cell leukemia in transgenic zebrafish

Abstract

Activating mutations in the NOTCH1 gene have been found in about 60% of patients with T-cell acute lymphoblastic leukemia (T-ALL). In order to study the molecular mechanisms by which altered Notch signaling induces leukemia, a zebrafish model of human NOTCH1-induced T-cell leukemia was generated. Seven of sixteen mosaic fish developed a T-cell lymphoproliferative disease at about 5 months. These neoplastic cells extensively invaded tissues throughout the fish and caused an aggressive and lethal leukemia when transplanted into irradiated recipient fish. However, stable transgenic fish exhibited a longer latency for leukemia onset. When the stable transgenic line was crossed with another line overexpressing the zebrafish bcl2 gene, the leukemia onset was dramatically accelerated, indicating synergy between the Notch pathway and the bcl2-mediated antiapoptotic pathway. Reverse transcription-polymerase chain reaction analysis showed that Notch target genes such as her6 and her9 were highly expressed in NOTCH1-induced leukemias. The ability of this model to detect a strong interaction between NOTCH1 and bcl2 suggests that genetic modifier screens have a high likelihood of revealing other genes that can cooperate with NOTCH1 to induce T-ALL.

Catch of the day: zebrafish as a human cancer model

“…Overexpression of TEL-AML1 led to the development of infiltrating B-lineage leukemia while rag2-mediated Notch overexpression resulted in T-cell leukemia. Both cancers also displayed similar properties with respect to mammals (Sabaawy et al, 2006;Chen et al, 2007).…”

“…In a separate study, the same group showed that irradiation or dexamethasone-induced apoptosis of fish leukemic cells is dependent on bcl-2 gene function that also operates in mammalian forms of leukemia (Langenau et al, 2005b). Two independent studies used a similar approach to induce different subtypes of leukemia mediated by overexpression of the aberrant TEL-AML1 fusion protein using the ubiquitous b-actin promoter or overexpression of Notch using the rag2 promoter (Sabaawy et al, 2006;Chen et al, 2007). Overexpression of TEL-AML1 led to the development of infiltrating B-lineage leukemia while rag2-mediated Notch overexpression resulted in T-cell leukemia.…”

p53 and Notch signaling in chronic lymphocytic leukemia: clues to identifying novel therapeutic strategies

“…47 Targeted expression of the active form of Notch 1 to immature T cells in a zebrafish transgenic model resulted in the development of T-cell leukemias. 48 The presence of Notch mutations are counterintuitively predictive of good initial therapeutic responses, although not of outcome. [49][50][51] Therapeutic strategies that combine inhibition of Notch processing by g-secretase inhibitors ( Figure 2) with glucocorticoids may be of value in the treatment of T-ALL.…”

Zebrafish as a Cancer Model

“…In another leukemia model, the knowledge was used that activating mutations in NOTCH1 are found in f60% of T-cell acute lymphoblastic leukemia. Zebrafish expressing constitutively active human NOTCH under the rag2 promotor developed T-cell leukemia at 5 to 11 months in f40% of the cases (39). When crossing these fish with the bcl2-overexpressing line (38), disease onset was accelerated and the leukemias were not radiation sensitive anymore, as apoptosis was inhibited.…”