BCL-2 Inhibitor ABT-737 Effectively Targets Leukemia-Initiating Cells with Differential Regulation of Relevant Genes Leading to Extended Survival in a NRAS/BCL-2 Mouse Model of High Risk-Myelodysplastic Syndrome
Abastract
1. Introduction
2. Results
2.1. ABT-737 Treatment Prolongs Survival in HR-MDS Transgenic Mice
2.2. ABT-737 Treatment Targets Leukemia Initiating Cells (LICs) and Primitive Progenitors
2.3. ABT-737 Treatment Induced Reduced Apoptosis in the BM, Increased Apoptosis and Inhibition of Cell Proliferation in the Liver and Spleen of HR-MDS Transgenic Mice
2.4. ABT-737 Induced Inhibition of BCL-2 Reduces RAS Activity in Sca1+ Cells
2.5. ABT-737 Treatment Induces Regulation of Pathways Implicated in Cell Survival, Proliferation and Stem Cell Regulation in HR-MDS Mice
3. Discussion
4. Materials and Methods
4.1. Transgenic Mice
4.2. ABT-737
4.3. Tissue and Cell Preparation, Flow Cytometry, Incucyte
4.4. Secondary Transplantation
4.5. Progenitor Colony Assay
4.6. Immunofluorescence and Confocal Microscopy
4.7. Mitochondrial Membrane Potential (MMP)
4.8. SPECT
4.8.1. ANX-Labeling
4.8.2. ANX-Scintigraphy
4.9. TUNEL
4.10. RAS Activation Assays and Western Blotting
4.11. Cell Preparation and RNA Extraction
4.12. Affymetrix Exon Array Hybridization
4.13. Array Data
4.14. RQ-PCR
4.15. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Apoptosis related genes regulated | |||
---|---|---|---|
Gene symbol | Regulation | Fold change | p value |
Sgk1 | up | 1.67 | 2.05 × 10−2 |
E2f2 | up | 2.06 | 2.12 × 10−2 |
Osm | up | 2.26 | 3.18 × 10−2 |
Rybp | up | 1.85 | 3.48 × 10−2 |
Ripk3 | up | 1.68 | 3.62 × 10−2 |
Rnf130 | up | 1.57 | 4.72 × 10−3 |
Gpx1 | up | 1.76 | 7.96 × 10−3 |
Bcl2l12 | up | 1.79 | 1.63 × 10−2 |
App | up | 2.46 | 3.79 × 10−2 |
Tnfrsf21 | up | 2.02 | 4.42 × 10−2 |
Pdcd5 | up | 1.65 | 1.82 × 10−2 |
Apaf1 | up | 1.62 | 3.56 × 10−2 |
Mfsd10 | up | 1.53 | 1.33 × 10−2 |
Pdcl3 | up | 1.50 | 2.26 × 10−3 |
Ckap2 | up | 1.91 | 2.50 × 10−2 |
Casp1 | up | 1.77 | 2.25 × 10−3 |
Bcl2a1a | up | 2.00 | 2.85 × 10−2 |
G2e3 | up | 1.89 | 1.74 × 10−3 |
Birc5 | up | 2.45 | 2.10 × 10−2 |
C1d | up | 1.52 | 1.07 × 10−2 |
Sgpl1 | up | 1.56 | 3.36 × 10−2 |
Bak1 | up | 1.97 | 1.49 × 10−2 |
Hipk2 | up | 1.51 | 3.38 × 10−2 |
Naip2 | up | 1.81 | 2.77 × 10−3 |
Rnf144b | up | 1.51 | 1.28 × 10−2 |
Pten | up | 1.98 | 4.07 × 10−3 |
Csf2rb | up | 2.48 | 1.18 × 10−2 |
Pik3cg | up | 1.62 | 3.48 × 10−3 |
Chp1 | up | 1.85 | 5.80 × × 10−4 |
Csf2rb2 | up | 1.73 | 2.07 × 10−2 |
Cxcr2 | up | 4.98 | 1.37 × 10−2 |
Wwox | down | 1.60 | 5.05 × 10−3 |
Eif2ak3 | down | 1.54 | 9.38 × 10−3 |
Fasl | down | 2.33 | 3.27 × 10−2 |
Lck | down | 1.68 | 3.46 × 10−2 |
Dyrk2 | down | 1.63 | 8.96 × × 10−4 |
Trib3 | down | 1.51 | 1.59 × 10−2 |
Sod1 | down | 1.54 | 4.83 × × 10−4 |
Fas | down | 1.54 | 2.01 × 10−2 |
Csrnp2 | down | 1.7 | 2.16 × 10−2 |
Splice related genes regulated | |||
Gene Symbol | Regulation | Fold-Change | p-Value |
Rsrc1 | up | 1.55 | 3.59 × 10−2 |
Gemin6 | up | 1.97 | 2.50 × 10−2 |
Gemin7 | up | 1.66 | 5.08 × 10−3 |
Lgals3 | up | 4.29 | 1.75 × 10−2 |
Lsm6 | up | 1.62 | 3.69 × 10−2 |
Zrsr2 | up | 1.71 | 4.37 × 10−2 |
Snrnp27 | up | 1.59 | 3.39 × 10−2 |
Snrpd2 | up | 1.76 | 4.59 × 10−2 |
Lsm10 | up | 1.90 | 1.28 × 10−3 |
Wbp4 | up | 1.85 | 1.67 × 10−2 |
Isy1 | down | 1.62 | 3.51 × 10−2 |
Pnn | down | 1.91 | 1.19 × 10−2 |
Prpf38b | down | 1.54 | 1.56 × 10−2 |
Rbm20 | down | 1.73 | 1.36 × 10−2 |
Rbfox1 | down | 1.50 | 6.72 × 10−3 |
Snrnp48 | down | 1.50 | 3.85 × 10−2 |
Tut1 | down | 1.73 | 2.19 × 10−2 |
Cell cycle related genes regulated | |||
Gene symbol | Regulation | Fold change | p value |
Cdk2 | up | 1.72 | 1.10 × 10−2 |
Ccne2 | up | 1.76 | 2.18 × 10−2 |
Cdc6 | up | 1.51 | 4.07 × 10−2 |
E2f2 | up | 2.06 | 2.12 × 10−2 |
Mapk13 | up | 3.06 | 3.22 × 10−2 |
Ccnb2 | up | 2.25 | 3.62 × 10−2 |
Cdca8 | up | 1.90 | 4.16 × 10−2 |
Ccna2 | up | 2.51 | 2.04 × 10−2 |
Cdk1 | up | 2.27 | 9.20 × 10−3 |
Cdkn2d | up | 2.01 | 5.12 × 10−3 |
Cdkn2c | up | 2.08 | 1.20 × 10−2 |
Ccnd3 | up | 1.88 | 2.09 × 10−2 |
Cdca3 | up | 2.24 | 1.91 × 10−2 |
Cdc25a | up | 1.92 | 1.95 × 10−2 |
Cdkn3 | up | 2.43 | 2.91 × 10−2 |
Mapk3 | up | 1.89 | 2.36 × 10−2 |
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Gorombei, P.; Guidez, F.; Ganesan, S.; Chiquet, M.; Pellagatti, A.; Goursaud, L.; Tekin, N.; Beurlet, S.; Patel, S.; Guerenne, L.; et al. BCL-2 Inhibitor ABT-737 Effectively Targets Leukemia-Initiating Cells with Differential Regulation of Relevant Genes Leading to Extended Survival in a NRAS/BCL-2 Mouse Model of High Risk-Myelodysplastic Syndrome. Int. J. Mol. Sci. 2021, 22, 10658. https://doi.org/10.3390/ijms221910658
Gorombei P, Guidez F, Ganesan S, Chiquet M, Pellagatti A, Goursaud L, Tekin N, Beurlet S, Patel S, Guerenne L, et al. BCL-2 Inhibitor ABT-737 Effectively Targets Leukemia-Initiating Cells with Differential Regulation of Relevant Genes Leading to Extended Survival in a NRAS/BCL-2 Mouse Model of High Risk-Myelodysplastic Syndrome. International Journal of Molecular Sciences. 2021; 22(19):10658. https://doi.org/10.3390/ijms221910658
Chicago/Turabian StyleGorombei, Petra, Fabien Guidez, Saravanan Ganesan, Mathieu Chiquet, Andrea Pellagatti, Laure Goursaud, Nilgun Tekin, Stephanie Beurlet, Satyananda Patel, Laura Guerenne, and et al. 2021. "BCL-2 Inhibitor ABT-737 Effectively Targets Leukemia-Initiating Cells with Differential Regulation of Relevant Genes Leading to Extended Survival in a NRAS/BCL-2 Mouse Model of High Risk-Myelodysplastic Syndrome" International Journal of Molecular Sciences 22, no. 19: 10658. https://doi.org/10.3390/ijms221910658