Understanding the TCL1 oncogene has provided valuable insights for gaining a better understanding of the causal relationship between leukemia and T-cell defects of the immune system. Altered pathways and malignant transformations activated by mutation within the TCL1 oncogene in patients are accurately represented by the TCL1 transgenic mouse model. This animal model has been widely validated for progressive immunotherapy studies. As one of the most common forms of leukemia in adults, chronic lymphocytic leukemia (CLL), which remains incurable, is a fitting model cancer for deliberation.

The deregulated expression of TCL1 in transgenic mice creates a disorder that greatly resembles chronic lymphocytic leukemia in humans. Findings validate the TCL1 mouse model as a means for immunotherapeutic discovery to combat immune-suppressive disease mechanisms.

For example, the demonstrated cytotoxicity of immunomodulatory drugs toward leukemia cells, including lenalidomide and fludarabine, is evident in both the TCL1 model and in human CLL. Additionally, the targets of these drugs in the mouse model for CLL (which are the same in human CLL) which include anti-apoptotic proteins, demonstrate the relevance of these therapeutic agents. Interestingly, the mouse model of CLL and human CLL both develop an eventual resistance to the drug fludarabine. Other drug responses, or lack thereof, are mimicked between TCL1 transgenic mice and with human CLL.

The pathways of gene expression altered by the mutated TCL1 gene give rise to malignant transformations. TCL1 proteins found in T-cells boost protein kinase B activity (also known as PKB or AKT), which is involved in multiple processes ithat are involved in cellular proliferation, and is often implicated in tumorigenesis. AKT1 and TCL1 interact directly within leukemic T-cells; introducing TCL1 in transgenic mice leads to increased blood-lymphocyte counts and consequent increase in the size of the lymphoid organs, a condition which is also seen in human CLL patients.

Studies of other antigens found on chronic lymphocytic leukemia B cells, such as Receptor tyrosine kinase-like orphan receptor 1 (ROR1), shed light on other pathways that may impact the progresson of CLL. Progeny of ROR1 and TCL1 mice, for instance, demonstrate higher levels of AKT than in TCL1 mice alone. In addition, TCL1 transgenic mice have been instrumental in uncovering a number of causal relationships that aid in the development of immunotherapeutic drugs.

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Categories: Oncology

Tags: animal model, Lymphocytic Leukemia, TCL1