TAL1/SCL is downregulated upon histone deacetylase inhibition in T-cell acute lymphoblastic leukemia cells

Abstract

The transcription factor T-cell acute lymphocytic leukemia (TAL)-1 is a major T-cell oncogene associated with poor prognosis in T-cell acute lymphoblastic leukemia (T-ALL). TAL1 binds histone deacetylase 1 and incubation with histone deacetylase inhibitors (HDACis) promotes apoptosis of leukemia cells obtained from TAL1 transgenic mice. Here, we show for the first time that TAL1 protein expression is strikingly downregulated upon histone deacetylase inhibition in T-ALL cells. This is due to decreased TAL1 gene transcription in cells with native TAL1 promoter, and due to impaired TAL1 mRNA translation in cells that harbor the TAL1 d microdeletion and consequently express TAL1 under the control of the SCL/ TAL1 interrupting locus (SIL) promoter. Notably, HDACi-triggered apoptosis of T-ALL cells is significantly reversed by TAL1 forced overexpression. Our results indicate that the HDACi-mediated apoptotic program in T-ALL cells is partially dependent on their capacity to downregulate TAL1 and provide support for the therapeutic use of HDACi in T-ALL.

Genetic interaction between Kit and Scl

“…23,47,48 In contrast, the survival of late erythroid cells 20 and of monocytes 39 does not depend on SCL function, indicating that SCL may have different functions in progenitors and mature cells. We have previously shown that Kit is a target of transcription activation by SCL.…”

MiR-146b negatively regulates migration and delays progression of T-cell acute lymphoblastic leukemia

“…TAL1 expression is shut down upon T-cell lineage commitment21 and its aberrant expression in committed T-cell precursors is associated with leukemogenesis, with TAL1 overexpression occurring in more than 60% of T-ALL patients222324. Although a considerable number of TAL1 downstream target genes have been identified to date1223252627282930313233343536 validation and characterization of their functional involvement in TAL1-mediated leukemogenesis remain fragmentary.…”

Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia

“…[1][2][3][4][5] Survival rates at 5 years for children and adolescents with T-ALL are 70-75%, whereas for adults the rates are 35-40%. 6,7 Therefore, there is a need for novel and less toxic treatment strategies targeting aberrantly activated signaling pathways that increase proliferation, survival and drug resistance of T-ALL cells.…”