TY - JOUR
T1 - 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
AU - Gorombei, Petra
AU - Guidez, Fabien
AU - Ganesan, Saravanan
AU - Chiquet, Mathieu
AU - Pellagatti, Andrea
AU - Goursaud, Laure
AU - Tekin, Nilgun
AU - Beurlet, Stephanie
AU - Patel, Satyananda
AU - Guerenne, Laura
AU - Le Pogam, Carole
AU - Setterblad, Niclas
AU - de la Grange, Pierre
AU - Leboeuf, Christophe
AU - Janin, Anne
AU - Noguera, Maria Elena
AU - Sarda-Mantel, Laure
AU - Merlet, Pascale
AU - Boultwood, Jacqueline
AU - Konopleva, Marina
AU - Andreeff, Michael
AU - West, Robert
AU - Pla, Marika
AU - Adès, Lionel
AU - Fenaux, Pierre
AU - Krief, Patricia
AU - Chomienne, Christine
AU - Omidvar, Nader
AU - Padua, Rose Ann
N1 - Publisher Copyright:
© 2021 by the author. Licensee MDPI, Basel, Switzerland.
PY - 2021/10/1
Y1 - 2021/10/1
N2 - During transformation, myelodysplastic syndromes (MDS) are characterized by reducing apoptosis of bone marrow (BM) precursors. Mouse models of high risk (HR)-MDS and acute myelogenous leukemia (AML) post-MDS using mutant NRAS and overexpression of human BCL-2, known to be poor prognostic indicators of the human diseases, were created. We have reported the efficacy of the BCL-2 inhibitor, ABT-737, on the AML post-MDS model; here, we report that this BCL-2 inhibitor also significantly extended survival of the HR-MDS mouse model, with reductions of BM blasts and lineage negative/Sca1+/KIT+ (LSK) cells. Secondary transplants showed increased survival in treated compared to untreated mice. Unlike the AML model, BCL-2 expression and RAS activity decreased following treatment and the RAS:BCL-2 complex remained in the plasma mem-brane. Exon-specific gene expression profiling (GEP) of HR-MDS mice showed 1952 differentially regulated genes upon treatment, including genes important for the regulation of stem cells, differ-entiation, proliferation, oxidative phosphorylation, mitochondrial function, and apoptosis; relevant in human disease. Spliceosome genes, found to be abnormal in MDS patients and downregulated in our HR-MDS model, such as Rsrc1 and Wbp4, were upregulated by the treatment, as were genes involved in epigenetic regulation, such as DNMT3A and B, upregulated upon disease progression and downregulated upon treatment.
AB - During transformation, myelodysplastic syndromes (MDS) are characterized by reducing apoptosis of bone marrow (BM) precursors. Mouse models of high risk (HR)-MDS and acute myelogenous leukemia (AML) post-MDS using mutant NRAS and overexpression of human BCL-2, known to be poor prognostic indicators of the human diseases, were created. We have reported the efficacy of the BCL-2 inhibitor, ABT-737, on the AML post-MDS model; here, we report that this BCL-2 inhibitor also significantly extended survival of the HR-MDS mouse model, with reductions of BM blasts and lineage negative/Sca1+/KIT+ (LSK) cells. Secondary transplants showed increased survival in treated compared to untreated mice. Unlike the AML model, BCL-2 expression and RAS activity decreased following treatment and the RAS:BCL-2 complex remained in the plasma mem-brane. Exon-specific gene expression profiling (GEP) of HR-MDS mice showed 1952 differentially regulated genes upon treatment, including genes important for the regulation of stem cells, differ-entiation, proliferation, oxidative phosphorylation, mitochondrial function, and apoptosis; relevant in human disease. Spliceosome genes, found to be abnormal in MDS patients and downregulated in our HR-MDS model, such as Rsrc1 and Wbp4, were upregulated by the treatment, as were genes involved in epigenetic regulation, such as DNMT3A and B, upregulated upon disease progression and downregulated upon treatment.
KW - ABT-737
KW - BCL-2
KW - Gene regulation
KW - HR-MDS
UR - http://www.scopus.com/inward/record.url?scp=85116023612&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85116023612&partnerID=8YFLogxK
U2 - 10.3390/ijms221910658
DO - 10.3390/ijms221910658
M3 - Article
C2 - 34638998
AN - SCOPUS:85116023612
SN - 1661-6596
VL - 22
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 19
M1 - 10658
ER -