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Published on: June 12, 2021
Dicer1 imparts essential survival cues in Notch-driven T-ALL via miR-21-mediated tumor suppressor Pdcd4 repression
Fabian Junker1, Antoine Chabloz1, Ute Koch1
1Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, Swiss Experimental Cancer Research Institute, Lausanne, Switzerland.
Abstract:
The modulatory function of individual microRNAs (miRNAs) in Notch-driven T-cell acute lymphoblastic leukemias (T-ALLs) has recently been established. Although protumorigenic and tumor-suppressive miRNAs are implicated in disease onset in murine models of Notch-driven T-cell leukemia, whether Dicer1-processed miRNAs are essential for Notch-driven T-ALL is currently unknown. Here we used conditional and inducible genetic loss-of-function approaches to test whether the development and maintenance of Notch-driven T-ALL was dependent on Dicer1 function. Mice with specific inactivation of both Dicer1 alleles in the T-cell lineage did not develop Notch-driven T-ALL. In contrast, loss of 1 functional Dicer1 allele did not significantly perturb T-ALL onset and tumor progression. Inducible inactivation of Dicer1 in early stage polyclonal T-ALL cells was sufficient to abrogate T-ALL progression in leukemic mice, whereas late-stage monoclonal T-ALL cells were counterselected against loss of Dicer1. Lineage-tracing experiments revealed that Dicer1 deficiency led to the induction of apoptosis in T-ALL cells, whereas cell cycle progression remained unaltered. Through microarray-based miRNA profiling, we identified miR-21 as a previously unrecognized miRNA deregulated in both mouse and human T-ALL. Herein, we demonstrate that miR-21 regulates T-ALL cell survival via repression of the tumor suppressor Pdcd4.
Insights
Dicer1-processed microRNAs are essential for Notch-driven T-cell acute lymphoblastic leukemia (T-ALL) development and maintenance. Loss of Dicer1 function induces apoptosis in T-ALL cells, highlighting its critical role in leukemia progression.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Individual microRNAs (miRNAs) modulate Notch-driven T-cell acute lymphoblastic leukemias (T-ALLs).
- The essential role of Dicer1-processed miRNAs in Notch-driven T-ALL remains unclear.
- Tumorigenic and tumor-suppressive miRNAs are implicated in T-ALL onset in murine models.
Purpose of the Study:
- To investigate the dependency of Notch-driven T-ALL development and maintenance on Dicer1 function.
- To determine if Dicer1 is essential for T-ALL progression using genetic loss-of-function models.
- To identify specific miRNAs involved in T-ALL pathogenesis.
Main Methods:
- Conditional and inducible genetic loss-of-function approaches in mice.
- Inactivation of Dicer1 alleles in T-cell lineage.
- Microarray-based miRNA profiling.
- Lineage-tracing experiments.
Main Results:
- Complete inactivation of Dicer1 alleles prevented Notch-driven T-ALL development.
- Inducible Dicer1 inactivation abrogated early-stage T-ALL progression, but late-stage cells were counterselected.
- Dicer1 deficiency induced apoptosis in T-ALL cells without altering cell cycle progression.
- miR-21 was identified as a deregulated miRNA in mouse and human T-ALL, regulating T-ALL cell survival via Pdcd4 repression.
Conclusions:
- Dicer1 is essential for the development and maintenance of Notch-driven T-ALL.
- Dicer1-processed miRNAs are critical for T-ALL cell survival.
- miR-21 plays a significant role in T-ALL pathogenesis by targeting the tumor suppressor Pdcd4.
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