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Novel strategy for rapid functional in vivo validation of oncogenic drivers in haematological malignancies

Tim Pieters (UGent) , Sara T'Sas (UGent) , Lisa Demoen (UGent) , André Pedro Pinto De Almeida (UGent) , Lieven Haenebalcke (UGent) , Filip Matthijssens (UGent) , Kelly Lemeire (UGent) , Jinke D'Hont (UGent) , Frédérique Vanrockeghem (UGent) , Tino Hochepied (UGent) , et al.
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Abstract
In cancer research, it remains challenging to functionally validate putative novel oncogenic drivers and to establish relevant preclinical models for evaluation of novel therapeutic strategies. Here, we describe an optimized and efficient pipeline for the generation of novel conditional overexpression mouse models in which putative oncogenes, along with an eGFP/Luciferase dual reporter, are expressed from the endogenous ROSA26 (R26) promoter. The efficiency of this approach was demonstrated by the generation and validation of novel R26 knock-in (KI) mice that allow conditional overexpression of Jarid2, Runx2, MN1 and a dominant negative allele of ETV6. As proof of concept, we confirm that MN1 overexpression in the hematopoietic lineage is sufficient to drive myeloid leukemia. In addition, we show that T-cell specific activation of MN1 in combination with loss of Pten increases tumour penetrance and stimulates the formation of Lyl1(+) murine T-cell lymphoblastic leukemias or lymphomas (T-ALL/T-LBL). Finally, we demonstrate that these luciferase-positive murine AML and T-ALL/T-LBL cells are transplantable into immunocompromised mice allowing preclinical evaluation of novel antileukemic drugs in vivo.
Keywords
ACUTE MYELOID-LEUKEMIA, LYMPHOBLASTIC-LEUKEMIA, EXPRESSION SIGNATURES, PTEN, GENE, MN1, OVEREXPRESSION, MOUSE, MICE, RECOMBINATION

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MLA
Pieters, Tim et al. “Novel Strategy for Rapid Functional in Vivo Validation of Oncogenic Drivers in Haematological Malignancies.” SCIENTIFIC REPORTS 9 (2019): n. pag. Print.
APA
Pieters, T., T’Sas, S., Demoen, L., Pedro Pinto De Almeida, A., Haenebalcke, L., Matthijssens, F., Lemeire, K., et al. (2019). Novel strategy for rapid functional in vivo validation of oncogenic drivers in haematological malignancies. SCIENTIFIC REPORTS, 9.
Chicago author-date
Pieters, Tim, Sara T’Sas, Lisa Demoen, André Pedro Pinto De Almeida, Lieven Haenebalcke, Filip Matthijssens, Kelly Lemeire, et al. 2019. “Novel Strategy for Rapid Functional in Vivo Validation of Oncogenic Drivers in Haematological Malignancies.” Scientific Reports 9.
Chicago author-date (all authors)
Pieters, Tim, Sara T’Sas, Lisa Demoen, André Pedro Pinto De Almeida, Lieven Haenebalcke, Filip Matthijssens, Kelly Lemeire, Jinke D’Hont, Frédérique Vanrockeghem, Tino Hochepied, Béatrice Lintermans, Lindy Reunes, Tim Lammens, Geert Berx, Jody J. Haigh, Steven Goossens, and Pieter Van Vlierberghe. 2019. “Novel Strategy for Rapid Functional in Vivo Validation of Oncogenic Drivers in Haematological Malignancies.” Scientific Reports 9.
Vancouver
1.
Pieters T, T’Sas S, Demoen L, Pedro Pinto De Almeida A, Haenebalcke L, Matthijssens F, et al. Novel strategy for rapid functional in vivo validation of oncogenic drivers in haematological malignancies. SCIENTIFIC REPORTS. 2019;9.
IEEE
[1]
T. Pieters et al., “Novel strategy for rapid functional in vivo validation of oncogenic drivers in haematological malignancies,” SCIENTIFIC REPORTS, vol. 9, 2019.
@article{8625761,
  abstract     = {In cancer research, it remains challenging to functionally validate putative novel oncogenic drivers and to establish relevant preclinical models for evaluation of novel therapeutic strategies. Here, we describe an optimized and efficient pipeline for the generation of novel conditional overexpression mouse models in which putative oncogenes, along with an eGFP/Luciferase dual reporter, are expressed from the endogenous ROSA26 (R26) promoter. The efficiency of this approach was demonstrated by the generation and validation of novel R26 knock-in (KI) mice that allow conditional overexpression of Jarid2, Runx2, MN1 and a dominant negative allele of ETV6. As proof of concept, we confirm that MN1 overexpression in the hematopoietic lineage is sufficient to drive myeloid leukemia. In addition, we show that T-cell specific activation of MN1 in combination with loss of Pten increases tumour penetrance and stimulates the formation of Lyl1(+) murine T-cell lymphoblastic leukemias or lymphomas (T-ALL/T-LBL). Finally, we demonstrate that these luciferase-positive murine AML and T-ALL/T-LBL cells are transplantable into immunocompromised mice allowing preclinical evaluation of novel antileukemic drugs in vivo.},
  articleno    = {10577},
  author       = {Pieters, Tim and T'Sas, Sara and Demoen, Lisa and Pedro Pinto De Almeida, André and Haenebalcke, Lieven and Matthijssens, Filip and Lemeire, Kelly and D'Hont, Jinke and Vanrockeghem, Frédérique and Hochepied, Tino and Lintermans, Béatrice and Reunes, Lindy and Lammens, Tim and Berx, Geert and Haigh, Jody J. and Goossens, Steven and Van Vlierberghe, Pieter},
  issn         = {2045-2322},
  journal      = {SCIENTIFIC REPORTS},
  keywords     = {ACUTE MYELOID-LEUKEMIA,LYMPHOBLASTIC-LEUKEMIA,EXPRESSION SIGNATURES,PTEN,GENE,MN1,OVEREXPRESSION,MOUSE,MICE,RECOMBINATION},
  language     = {eng},
  pages        = {12},
  title        = {Novel strategy for rapid functional in vivo validation of oncogenic drivers in haematological malignancies},
  url          = {http://dx.doi.org/10.1038/s41598-019-46853-x},
  volume       = {9},
  year         = {2019},
}

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