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Aberrant RNA degradation in T-cell leukemia

Final Report Summary - ART (Aberrant RNA degradation in T-cell leukemia)

Cancer is a complex disease that is caused by the accumulation of mutations in various pathways, which lead to a global change in gene expression in the cancer cells. These gene expression changes can be the result of signaling defects, alterations in transcription factors or epigenetic factors, or RNA splicing changes. We have recently discovered that also RNA stability can be altered and we studied how this can affect cancer development.

In this project we performed studies in Drosophila melanogaster (the fruitfly), where we used an eye cancer model to determine the role of several proteins implicated in the regulation of RNA stability (Not1, Not2, Not3, twin, pop2 = CCR4-NOT complex). Our data show that inactivation of these proteins enhances eye cancer development in the fruitfly models as can be observed by increased folding and disorganisation in the eye. Conversely, overexpression of these proteins could partially reduce cancer development in the eye cancer model, illustrating that the CCR4-NOT complex has tumor suppressor activity.
Mechanistically, we found that loss of the CCR4-NOT complex is associated with upregulation of genes implicated in DNA replication and ribosome biogenesis. These results were also confirmed in human cancer cell lines and indicate that the machinery implicated in regulating RNA stability suppresses tumor development.

We also studied the role of Cnot3 (the mouse homolog of Not3), one of the proteins that is recurrently mutated in T-cell acute lymphoblastic leukemia, in normal T-cell development as well as in leukemia development. Loss of Cnot3 was associated with a decrease in the amount of P-bodies, foci that are present in the cytoplasm and are involved in RNA degradation. Loss of Cnot3 also resulted in a clear differentiation block of the developing T cells, resulting in accumulation of immature T cells in the thymus. To study a possible role for Cnot3 in leukemia development, we have used three different T-cell leukemia models. We used a simple leukemia model based on the overexpression of a NOTCH1 mutant, and two more complex models based on the co-expression of TLX1 and NUP214-ABL1 on one hand and co-expression of HOXA9 and JAK3(M511I) on the other hand. Despite the use of these various models, we could not demonstrate an important role for loss of Cnot3 in the development of leukemia. We did observe a clear cooperation between TLX1 and NUP214-ABL1 in the development of leukemia, and we could mechanistically link this to an increased activation of enhancer elements in the DNA by TLX1 and STAT5 (downstream of NUP214-ABL1), but loss of Cnot3 did not further affect this. Similarly, we demonstrated a clear cooperation between JAK3 signaling and HOXA9, but again loss of Cnot3 did not have additional effects.

In conclusion, our data from Drosophila melanogaster (fruitfly) define the CCR4-NOT complex as a tumor suppressor complex and link defects in RNA degradation to cancer development. Loss of Cnot3, one of the members of the CCR4-NOT complex, is required for normal T cell development, but a clear role for this protein in leukemia development could not yet be illustrated. Loss of CNOT3 in human cancer cell lines resulted in increased expression of genes implicated in DNA replication and ribosome biogenesis, which is a potential link to cancer development.