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Hh/Gli antagonist in acute myeloid leukemia with CBFA2T3-GLIS2 fusion gene
- Source :
- Journal of Hematology & Oncology, Vol 10, Iss 1, Pp 1-5 (2017), Journal of Hematology & Oncology
- Publication Year :
- 2017
- Publisher :
- Springer Science and Business Media LLC, 2017.
-
Abstract
- 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. Electronic supplementary material The online version of this article (doi:10.1186/s13045-017-0396-0) contains supplementary material, which is available to authorized users.
- Subjects :
- Myeloid
0301 basic medicine
Cancer Research
Oncogene Proteins, Fusion
Pyridines
Apoptosis
Hedgehog pathway
Fusion gene
Acute megakaryoblastic leukemia
0302 clinical medicine
Gene expression
Tumor Cells, Cultured
Acute myeloid leukemia
CBFA2T3-GLIS2
GANT61
Cell Cycle Checkpoints
Child
Down-Regulation
Hedgehog Proteins
Humans
Kruppel-Like Transcription Factors
Leukemia, Myeloid, Acute
Pyrimidines
Repressor Proteins
Tumor Suppressor Proteins
Zinc Finger Protein GLI1
Hematology
Molecular Biology
Oncology
Letter to the Editor
Oncogene Proteins
Leukemia
Cultured
CBFA2T3/GLIS2 Fusion Gene
Myeloid leukemia
lcsh:Diseases of the blood and blood-forming organs
Cell cycle
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Tumor Cells
Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA
030220 oncology & carcinogenesis
Acute
Biology
lcsh:RC254-282
NO
03 medical and health sciences
medicine
Fusion
lcsh:RC633-647.5
medicine.disease
Fusion protein
030104 developmental biology
Cancer research
DNMT1
Subjects
Details
- ISSN :
- 17568722
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- Journal of Hematology & Oncology
- Accession number :
- edsair.doi.dedup.....776e999d140b2de4a043498eb7223dc3