TY - JOUR
T1 - Hh/Gli antagonist in acute myeloid leukemia with CBFA2T3-GLIS2 fusion gene
AU - Masetti, Riccardo
AU - Bertuccio, Salvatore Nicola
AU - Astolfi, Annalisa
AU - Chiarini, Francesca
AU - Lonetti, Annalisa
AU - Indio, Valentina
AU - De Luca, Matilde
AU - Bandini, Jessica
AU - Serravalle, Salvatore
AU - Franzoni, Monica
AU - Pigazzi, Martina
AU - Martelli, Alberto Maria
AU - Basso, Giuseppe
AU - Locatelli, Franco
AU - Pession, Andrea
PY - 2017
Y1 - 2017
N2 - Background: CBFA2T3-GLIS2 is a fusion gene found in 17% of non-Down syndrome acute megakaryoblastic leukemia (non-DS AMKL, FAB M7) and in 8% of pediatric cytogenetically normal acute myeloid leukemia (CN-AML, in association with several French-American-British (FAB) subtypes). Children with AML harboring this aberration have a poor outcome, regardless of the FAB subtype. This fusion gene drives a peculiar expression pattern and leads to overexpression of some of Hedgehog-related genes. GLI-similar protein 2 (GLIS2) is closely related to the GLI family, the final effectors of classic Hedgehog pathway. These observations lend compelling support to the application of GLI inhibitors in the treatment of AML with the aberration CBFA2T3-GLIS2. GANT61 is, nowadays, the most potent inhibitor of GLI family proteins. Methods: We exposed to GANT61 AML cell lines and primary cells positive and negative for CBFA2T3-GLIS2 and analyzed the effect on cellular viability, induction of apoptosis, cell cycle, and expression profile. Results: As compared to AML cells without GLIS2 fusion, GANT61 exposure resulted in higher sensitivity of both cell lines and primary AML cells carrying CBFA2T3-GLIS2 to undergo apoptosis and G1 cell cycle arrest. Remarkably, gene expression studies demonstrated downregulation of GLIS2-specific signature genes in both treated cell lines and primary cells, in comparison with untreated cells. Moreover, chromatin immunoprecipitation analysis revealed direct regulation by GLIS2 chimeric protein of DNMT1 and DNMT3B, two genes implicated in important epigenetic functions. Conclusions: Our findings indicate that the GLI inhibitor GANT61 may be used to specifically target the CBFA2T3-GLIS2 fusion gene in pediatric AML.
AB - Background: CBFA2T3-GLIS2 is a fusion gene found in 17% of non-Down syndrome acute megakaryoblastic leukemia (non-DS AMKL, FAB M7) and in 8% of pediatric cytogenetically normal acute myeloid leukemia (CN-AML, in association with several French-American-British (FAB) subtypes). Children with AML harboring this aberration have a poor outcome, regardless of the FAB subtype. This fusion gene drives a peculiar expression pattern and leads to overexpression of some of Hedgehog-related genes. GLI-similar protein 2 (GLIS2) is closely related to the GLI family, the final effectors of classic Hedgehog pathway. These observations lend compelling support to the application of GLI inhibitors in the treatment of AML with the aberration CBFA2T3-GLIS2. GANT61 is, nowadays, the most potent inhibitor of GLI family proteins. Methods: We exposed to GANT61 AML cell lines and primary cells positive and negative for CBFA2T3-GLIS2 and analyzed the effect on cellular viability, induction of apoptosis, cell cycle, and expression profile. Results: As compared to AML cells without GLIS2 fusion, GANT61 exposure resulted in higher sensitivity of both cell lines and primary AML cells carrying CBFA2T3-GLIS2 to undergo apoptosis and G1 cell cycle arrest. Remarkably, gene expression studies demonstrated downregulation of GLIS2-specific signature genes in both treated cell lines and primary cells, in comparison with untreated cells. Moreover, chromatin immunoprecipitation analysis revealed direct regulation by GLIS2 chimeric protein of DNMT1 and DNMT3B, two genes implicated in important epigenetic functions. Conclusions: Our findings indicate that the GLI inhibitor GANT61 may be used to specifically target the CBFA2T3-GLIS2 fusion gene in pediatric AML.
KW - Acute megakaryoblastic leukemia
KW - Acute myeloid leukemia
KW - Hedgehog pathway
KW - GANT61
KW - CBFA2T3-GLIS2
KW - Acute megakaryoblastic leukemia
KW - Acute myeloid leukemia
KW - Hedgehog pathway
KW - GANT61
KW - CBFA2T3-GLIS2
UR - http://hdl.handle.net/10807/230077
U2 - 10.1186/s13045-017-0396-0
DO - 10.1186/s13045-017-0396-0
M3 - Article
SN - 1756-8722
VL - 10
SP - 1
EP - 5
JO - JOURNAL OF HEMATOLOGY & ONCOLOGY
JF - JOURNAL OF HEMATOLOGY & ONCOLOGY
ER -