Hh-Gli antagonist in acute myeloid leukemia with CBFA2T3-GLIS2 fusion geneReportar como inadecuado




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Journal of Hematology and Oncology

, 10:26

First Online: 21 January 2017Received: 19 November 2016Accepted: 10 January 2017DOI: 10.1186-s13045-017-0396-0

Cite this article as: Masetti, R., Bertuccio, S.N., Astolfi, A. et al. J Hematol Oncol 2017 10: 26. doi:10.1186-s13045-017-0396-0

Abstract

BackgroundCBFA2T3-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.

MethodsWe 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.

ResultsAs 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.

ConclusionsOur findings indicate that the GLI inhibitor GANT61 may be used to specifically target the CBFA2T3-GLIS2 fusion gene in pediatric AML.

KeywordsAcute myeloid leukemia Acute megakaryoblastic leukemia CBFA2T3-GLIS2 GANT61 Hedgehog pathway AbbreviationsAMLAcute myeloid leukemia

AURKAAurora A kinase

BMPBone morphogenic protein

ChIPChromatin immunoprecipitation

FABFrench-American-British

GLIS2GLI-similar protein 2

HHHedgehog

PIPropidium iodide

WST14-3-4 lodophenyl-2-4-nitrophenyl-2H-5-tetrazolio-1,3-benzene disulfonate

Electronic supplementary materialThe online version of this article doi:10.1186-s13045-017-0396-0 contains supplementary material, which is available to authorized users.

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Autor: Riccardo Masetti - Salvatore Nicola Bertuccio - Annalisa Astolfi - Francesca Chiarini - Annalisa Lonetti - Valentina Indio

Fuente: https://link.springer.com/







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