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A cooperative microRNA-tumor suppressor gene network in acute T-cell lymphoblastic leukemia (T-ALL)

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Abstract
Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes. In order to comprehensively assess the action of microRNAs (miRNAs) in T-ALL, we compared miRNA expression patterns in 50 human T-ALL samples and 5 subsets of normal T-cell progenitors with an unbiased miRNA library screen followed by computational target identification and functional assessment of the most relevant candidate miRNAs in a murine T-ALL model. Methods: Using high-throughput quantitative stem-loop RT-PCR, 430 miRNAs were profiled in a T-ALL patient cohort including 12 HOXA, 15 TAL/LMO, 10 TLX3 and 5 TLX1 rearranged patient samples as well as in 5 different subsets of sorted T-cell populations. An unbiased miRNA library screen was performed in c-MYC transduced MEFs, based upon rescue for c-MYC-induced apoptosis, followed by validation for individual miRNAs in FL5-12 lymphocytes and an in vivo T-ALL mouse model. Results: In addition to specific sets of differentially expressed miRNAs in the genetic T-ALL subgroups, we identified ten miRNAs which were highly expressed in the entire cohort of T-ALLs, i.e. miR-223, miR-19b, miR-20a, miR-92, miR-142-3p, miR-150, miR-93, miR-26a, miR-16 and miR-342. High expression of the latter subset of 10 miRNAs was confirmed in a series of 18 T-ALL cell lines. A comparison with purified normal T-cell populations revealed leukemia-specific increases in miR-223, and less so for miR-376 and miR-662. Subsequent cross-comparison with the results of a parallel unbiased miRNA library screen, allowed us to identify five miRNAs (miR-19b, miR-20a, miR-26a, miR-92, miR-223) capable of promoting T-ALL development in a NOTCH sensitized murine model. These miRNAs produce overlapping and cooperative effects on validated target genes with known tumor suppressor function in T-ALL, including IKAROS (IKZF1), PTEN, BIM/BCL2L11, PHF6, NF1 and FBXW7. Conclusion: A comprehensive and unbiased analysis of miRNA action in T-ALL reveals for the first time a cooperative role for a small subset of miRNAs in suppression of key T-ALL suppressor genes and opens the way to new miRNA therapeutic approaches for this disease.
Keywords
T-ALL, miRNA, tumor suppressor, Leukemia

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MLA
Mets, Evelien, Joni Van der Meulen, Konstantinos J Mavrakis, et al. “A Cooperative microRNA-tumor Suppressor Gene Network in Acute T-cell Lymphoblastic Leukemia (T-ALL).” Belgian Society of Human Genetics, 11th Annual Meeting, Abstracts. 2011. Print.
APA
Mets, E., Van der Meulen, J., Mavrakis, K. J., Wolfe, A. L., Taghon, T., Khan, A. A., Setty, M., et al. (2011). A cooperative microRNA-tumor suppressor gene network in acute T-cell lymphoblastic leukemia (T-ALL). Belgian Society of Human Genetics, 11th Annual meeting, Abstracts. Presented at the 11th Annual meeting of the Belgian Society of Human Genetics (BeSHG).
Chicago author-date
Mets, Evelien, Joni Van der Meulen, Konstantinos J Mavrakis, Andrew L Wolfe, Tom Taghon, Aly A Khan, Manu Setty, et al. 2011. “A Cooperative microRNA-tumor Suppressor Gene Network in Acute T-cell Lymphoblastic Leukemia (T-ALL).” In Belgian Society of Human Genetics, 11th Annual Meeting, Abstracts.
Chicago author-date (all authors)
Mets, Evelien, Joni Van der Meulen, Konstantinos J Mavrakis, Andrew L Wolfe, Tom Taghon, Aly A Khan, Manu Setty, Xiaoping Liu, Pieter Rondou, Peter Vandenberghe, Eric Delabesse, Yves Benoit, Nicholas Socci, Christine S Leslie, Bruce Poppe, Pieter Van Vlierberghe, Hans-Guido Wendel, and Franki Speleman. 2011. “A Cooperative microRNA-tumor Suppressor Gene Network in Acute T-cell Lymphoblastic Leukemia (T-ALL).” In Belgian Society of Human Genetics, 11th Annual Meeting, Abstracts.
Vancouver
1.
Mets E, Van der Meulen J, Mavrakis KJ, Wolfe AL, Taghon T, Khan AA, et al. A cooperative microRNA-tumor suppressor gene network in acute T-cell lymphoblastic leukemia (T-ALL). Belgian Society of Human Genetics, 11th Annual meeting, Abstracts. 2011.
IEEE
[1]
E. Mets et al., “A cooperative microRNA-tumor suppressor gene network in acute T-cell lymphoblastic leukemia (T-ALL),” in Belgian Society of Human Genetics, 11th Annual meeting, Abstracts, Louvain-La-Neuve, Belgium, 2011.
@inproceedings{5774383,
  abstract     = {Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes. In order to comprehensively assess the action of microRNAs (miRNAs) in T-ALL, we compared miRNA expression patterns in 50 human T-ALL samples and 5 subsets of normal T-cell progenitors with an unbiased miRNA library screen followed by computational target identification and functional assessment of the most relevant candidate miRNAs in a murine T-ALL model.
Methods: Using high-throughput quantitative stem-loop RT-PCR, 430 miRNAs were profiled in a T-ALL patient cohort including 12 HOXA, 15 TAL/LMO, 10 TLX3 and 5 TLX1 rearranged patient samples as well as in 5 different subsets of sorted T-cell populations. An unbiased miRNA library screen was performed in c-MYC transduced MEFs, based upon rescue for c-MYC-induced apoptosis, followed by validation for individual miRNAs in FL5-12 lymphocytes and an in vivo T-ALL mouse model.
Results: In addition to specific sets of differentially expressed miRNAs in the genetic T-ALL subgroups, we identified ten miRNAs which were highly expressed in the entire cohort of T-ALLs, i.e. miR-223, miR-19b, miR-20a, miR-92, miR-142-3p, miR-150, miR-93, miR-26a, miR-16 and miR-342. High expression of the latter subset of 10 miRNAs was confirmed in a series of 18 T-ALL cell lines. A comparison with purified normal T-cell populations revealed leukemia-specific increases in miR-223, and less so for miR-376 and miR-662. Subsequent cross-comparison with the results of a parallel unbiased miRNA library screen, allowed us to identify five miRNAs (miR-19b, miR-20a, miR-26a, miR-92, miR-223) capable of promoting T-ALL development in a NOTCH sensitized murine model. These miRNAs produce overlapping and cooperative effects on validated target genes with known tumor suppressor function in T-ALL, including IKAROS (IKZF1), PTEN, BIM/BCL2L11, PHF6, NF1 and FBXW7. 
Conclusion: A comprehensive and unbiased analysis of miRNA action in T-ALL reveals for the first time a cooperative role for a small subset of miRNAs in suppression of key T-ALL suppressor genes and opens the way to new miRNA therapeutic approaches for this disease.},
  author       = {Mets, Evelien and Van der Meulen, Joni and Mavrakis, Konstantinos J and Wolfe, Andrew L and Taghon, Tom and Khan, Aly A and Setty, Manu and Liu,  Xiaoping and Rondou, Pieter and Vandenberghe, Peter and Delabesse, Eric and Benoit, Yves and Socci, Nicholas and Leslie, Christine S and Poppe, Bruce and Van Vlierberghe, Pieter and Wendel, Hans-Guido and Speleman, Franki},
  booktitle    = {Belgian Society of Human Genetics, 11th Annual meeting, Abstracts},
  keywords     = {T-ALL,miRNA,tumor suppressor,Leukemia},
  language     = {eng},
  location     = {Louvain-La-Neuve, Belgium},
  title        = {A cooperative microRNA-tumor suppressor gene network in acute T-cell lymphoblastic leukemia (T-ALL)},
  year         = {2011},
}