Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Feb;184(3):337-347.
doi: 10.1111/bjh.15725. Epub 2018 Dec 28.

CBFA2T3-GLIS2-positive acute myeloid leukaemia. A peculiar paediatric entity

Riccardo Masetti  1 , Salvatore N Bertuccio  1 , Andrea Pession  1 , Franco Locatelli  2
Affiliations
Review

CBFA2T3-GLIS2-positive acute myeloid leukaemia. A peculiar paediatric entity

Riccardo Masetti et al. Br J Haematol. 2019 Feb.

Abstract

The scenario of paediatric acute myeloid leukaemia (AML), particularly non-Down syndrome acute megakaryoblastic leukaemia (non-DS-AMKL), has been recently revolutionized by the advent of large-scale, genomic sequencing technologies. In this changing landscape, a significantly relevant discovery has been represented by the identification of the CBFA2T3-GLIS2 fusion gene, which is the result of a cryptic inversion of chromosome 16. It is the most frequent chimeric oncogene identified to date in non-DS-AMKL, although it seems not to be exclusively restricted to the French-American-British M7 subgroup. The CBFA2T3-GLIS2 fusion gene characterizes a subtype of leukaemia that is specific to paediatrics, having never been identified in adults. It characterizes an extremely aggressive leukaemia, as the presence of this fusion is associated with a grim outcome in almost all of the case series reported, with overall survival rates ranging between 15% and 30%. Although the molecular basis that underlies this leukaemia subtype is still far from being completely elucidated, unique functional properties induced by CBFA2T3-GLIS2 in the leukaemogenesis driving process have been recently identified. We here review the peculiarities of CBFA2T3-GLIS2-positive AML, describing its intriguing clinical and biological behaviour and providing some challenging targeting opportunities.

Keywords: CBFA2T3-GLIS2; acute megakaryoblastic leukaemia; acute myeloid leukaemia; childhood leukaemia; leukaemia diagnosis.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Frequency of the most commonly chimeric gene fusions associated with paediatric non‐DS‐AMKL.
Figure 2
Figure 2
Representation of CBFA2T3‐GLIS2 fusion protein. Top panels: Common breakpoints in CBFA2T3 and GLIS2 genes at exons 11 and 3, respectively. Bottom panel: CBFA2T3‐Ex11/GLIS2‐Ex3 fusion protein with the retained domains. MYND, myeloid, nervy, and DEAF‐1; NHR, nervy homology regions; TAD, topologically associating domain; TRD, trans‐Repression Domain; ZF, zinc finger.
Figure 3
Figure 3
Mechanism of action of the CBFA2T3‐GLIS2 fusion protein. CBFA2T3‐GLIS2 is a part of a complex that binds to both promotor and enhancer sequences of many genes. In particular, it up‐regulates ERG and KIT expression and it down‐regulates GATA1 expression (Thirant et al, 2017a). Therefore, the fusion protein in one hit induces a block of differentiation and increases self‐renewal of haematopoietic cells driving leukaemia development.
Figure 4
Figure 4
Potential therapeutic target proposed to block leukaemia properties induced by the presence of CBFA2T3‐GLIS2. Aurora Kinase A (AURKA) inhibitors repress proliferation interfering with cell cycle and engages terminal differentiation of megakaryoblastic leukaemia cells (Thiollier et al, 2012). Small peptides, such as NC128, interfere with the NHR2 domain of CBFA2T3 moiety disrupting the complex and abrogating growth of AMKL cells in‐vivo (Thirant et al, 2017a). Treatment with GLI inhibitors interferes with expression pathway induced by CBFA2T3‐GLIS2. The specific interaction between GANT61 and GLIS2 remains to be formally demonstrated (Masetti et al, 2017). DiMF, dimethylfasudil.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Agyeman, A. , Jha, B.K. , Mazumdar, T. & Houghton, J.A. (2014) Mode and specificity of binding of the small molecule GANT61 to GLI determines inhibition of GLI‐DNA binding. Oncotarget, 5, 4492–4503. - PMC - PubMed
    1. Attanasio, M. , Uhlenhaut, N.H. , Sousa, V.H. , O'Toole, J.F. , Otto, E. , Anlag, K. , Klugmann, C. , Treier, A.C. , Helou, J. , Sayer, J.A. , Seelow, D. , Nürnberg, G. , Becker, C. , Chudley, A.E. , Nürnberg, P. , Hildebrandt, F. & Treier, M. (2007) Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis. Nature Genetics, 39, 1018–1024. - PubMed
    1. Bolouri, H. , Farrar, J.E. , Triche, T.J.R. , Ries, R.E. , Lim, E.L. , Alonzo, T.A. , Ma, Y. , Moore, R. , Mungall, A.J. , Marra, M.A. , Zhang, J. , Ma, X. , Liu, Y. , Liu, Y. , Auvil, J.M.G. , Davidsen, T.M. , Gesuwan, P. , Hermida, L.C. , Salhia, B. , Capone, S. , Ramsingh, G. , Zwaan, C.M. , Noort, S. , Piccolo, S.R. , Kolb, E.A. , Gamis, A.S. , Smith, M.A. , Gerhard, D.S. & Meshinchi, S. (2018) The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age‐specific mutational interactions. Nature Genetics, 24, 103–112. - PMC - PubMed
    1. Chyla, B.J. , Moreno‐Miralles, I. , Steapleton, M.A. , Thompson, M.A. , Bhaskara, S. , Engel, M. & Hiebert, S.W. (2008) Deletion of Mtg16, a target of t(16;21), alters hematopoietic progenitor cell proliferation and lineage allocation. Molecular and Cellular Biology, 28, 6234–6247. - PMC - PubMed
    1. Creutzig, U. , Reinhardt, D. , Diekamp, S. , Dworzak, M. , Stary, J. & Zimmermann, M. (2005) AML patients with Down syndrome have a high cure rate with AML‐BFM therapy with reduced dose intensity. Leukemia, 19, 1355–1360. - PubMed

Publication types

MeSH terms