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inv(16)(p13q24) CBFA2T3::GLIS2

Written2012-11Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

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ICD-Morpho 9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS
Atlas_Id 1624

Clinics and Pathology

Disease Acute megakaryoblastic leukemia (AMKL)
Note Acute megakaryoblastic leukemia (AMKL) was so far divided into three subgroups: AMKL arising in patients with Down syndrome (DS-AMKL), AMKL with a t(1;22)(p13;q13) giving rise of a 5' OTT - 3' MAL fusion gene, and "other" AMLKs, i.e. non Down syndrome / non t(1;22).
Two new categories have recently been individualized from the subgroup "non Down syndrome / non t(1;22)": the inv(16)(p13q24) CBFA2T3/GLIS2, and the t(11;12)(p15;p13) NUP98/KDM5A (Gruber et al., 2012; Thiollier et al., 2012).
Epidemiology Fourteen patients with data on sex and age are available; median age at diagnosis was 1 year - 1 year 4 months (range 6 months - 4 years 7 months).
The inv(16)(p13q24) CBFA2T3/GLIS2 was found in about 30% of non-Down syndrome pediatric AMKL cases (in 13 of 48 cases in Gruber et al., 2012, and 7 of 22 cases in Thiollier et al., 2012. So far, none of the 36 adult AMKL cases under study contained the chimeric transcript.
One patient had a Down syndrome (case SJAMLM7018 in Gruber et al., 2012), which shows that DS-AMKL and inv(16)-AMLK categories are not mutually exclusive.
Prognosis Subgroup of patients with a significantly worse overall survival at 5 years as compared to patients with AMKL that lacked this chimeric transcript (28% versus 42% in Gruber et al., 2012); fusion associated with treatment-refractory disease (Thiollier et al., 2012).


Cytogenetics Morphological This inversion of chromosome 16 is cryptic. The CBFA2T3/GLIS2 chimeric gene resulted from simple balanced inversions in three cases and from a complex rearrangement in one case (Gruber et al., 2012). A complex karyotype was found in 8 of the 12 cases with data on chromosomes; 2 remaining cases exhibited an apparently normal karyotype (Gruber et al., 2012).

Genes involved and Proteins

Gene NameGLIS2 (GLIS family zinc finger 2)
Location 16p13.3
Protein Kruppel-like zinc-finger protein. Transcription factor; repressor of the Hedgehog signaling pathway; repressor of the Wnt signaling pathway. GLIS2 has also been reported to localize to the primary cilium. A mutation GLIS2 has been linked to the development of nephronophthisis. Glis2 may act as a repressor of epithelial-mesenchymal transition (EMT) and EMT-related gene expression (Lichti-Kaiser et al., 2012).
Gene NameCBFA2T3 (core-binding factor, runt domain, alpha subunit 2; translocated to, 3)
Location 16q24.3
Protein Member of the "ETO" family. Functions as a transcriptional repressor via interaction with corepressor complexes; do not directly bind DNA, but interacts with transcription factors such as BCL6, PLZF, GFI1, ZNF651 and ZNF652 (Kumar et al., 2010).

Result of the chromosomal anomaly

Hybrid gene
Description 5' CBFA2T3 - 3' GLIS2. Fusion between exon 10 of CBFA2T3 and exon 3 of GLIS2 in 6 cases (Gruber et al., 2012); fusion between exon 11 of CBFA2T3 and exon 3 of GLIS2 in 1 case (Thiollier et al., 2012); fusion between exon 11 of CBFA2T3 and exon 1 of GLIS2 in 1 case (Gruber et al., 2012).
Fusion Protein
Description Retains the three CBFA2T3 N-terminal nervy homology regions (NHR) that mediate protein interactions and the five GLIS2 C-terminal domains (ZnF) responsible for interaction with DNA and transactivation. The MYND (myeloid, nervy, and Deaf-1 domain, class of zinc finger domain reported to interact with the N-CoR repressor complex) domain of CBFA2T3 is lost.
Oncogenesis This fusion between two transcriptional regulators results in aberrant expression of genes controlled either by CBFA2T3 or GLIS2 (Thiollier et al., 2012).
There is an homogenous gene expression signature including a strong expression of CD56. Among the differentially regulated genes are known targets of the Hedgehog pathway including BMP2, BMP4, GATA3, and CCND2. CBFA2T3/GLIS2 induces BMP signaling. Hedgehog and JAK-STAT pathways are significantly upregulated (Gruber et al., 2012; Thiollier et al., 2012). CBFA2T3/GLIS2 cells demonstrated enhanced self-renewal in vitro (Gruber et al., 2012). Aurora A kinase (AURKA) inhibitors can induce differentiation and inhibits proliferation of AMKL blasts (Thiollier et al., 2012).

To be noted

Additional cases are needed to delineate the epidemiology of this rare entity:
you are welcome to submit a paper to our new Case Report section.


An Inv(16)(p13.3q24.3)-Encoded CBFA2T3-GLIS2 Fusion Protein Defines an Aggressive Subtype of Pediatric Acute Megakaryoblastic Leukemia.
Gruber TA, Larson Gedman A, Zhang J, Koss CS, Marada S, Ta HQ, Chen SC, Su X, Ogden SK, Dang J, Wu G, Gupta V, Andersson AK, Pounds S, Shi L, Easton J, Barbato MI, Mulder HL, Manne J, Wang J, Rusch M, Ranade S, Ganti R, Parker M, Ma J, Radtke I, Ding L, Cazzaniga G, Biondi A, Kornblau SM, Ravandi F, Kantarjian H, Nimer SD, Dohner K, Dohner H, Ley TJ, Ballerini P, Shurtleff S, Tomizawa D, Adachi S, Hayashi Y, Tawa A, Shih LY, Liang DC, Rubnitz JE, Pui CH, Mardis ER, Wilson RK, Downing JR.
Cancer Cell. 2012 Nov 13;22(5):683-97. doi: 10.1016/j.ccr.2012.10.007.
PMID 23153540
CBFA2T3-ZNF651, like CBFA2T3-ZNF652, functions as a transcriptional corepressor complex.
Kumar R, Cheney KM, Neilsen PM, Schulz RB, Callen DF.
FEBS Lett. 2010 Mar 5;584(5):859-64. Epub 2010 Jan 30.
PMID 20116376
Gli-similar proteins: their mechanisms of action, physiological functions, and roles in disease.
Lichti-Kaiser K, ZeRuth G, Kang HS, Vasanth S, Jetten AM.
Vitam Horm. 2012;88:141-71. (REVIEW)
PMID 22391303
Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models.
Thiollier C, Lopez CK, Gerby B, Ignacimouttou C, Poglio S, Duffourd Y, Guegan J, Rivera-Munoz P, Bluteau O, Mabialah V, Diop M, Wen Q, Petit A, Bauchet AL, Reinhardt D, Bornhauser B, Gautheret D, Lecluse Y, Landman-Parker J, Radford I, Vainchenker W, Dastugue N, de Botton S, Dessen P, Bourquin JP, Crispino JD, Ballerini P, Bernard OA, Pflumio F, Mercher T.
J Exp Med. 2012 Oct 22;209(11):2017-31. doi: 10.1084/jem.20121343. Epub 2012 Oct 8.
PMID 23045605


This paper should be referenced as such :
Huret, JL
inv(16)(p13q24) CBFA2T3/GLIS2
Atlas Genet Cytogenet Oncol Haematol. 2013;17(3):199-200.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other genes implicated (Data extracted from papers in the Atlas) [ 1 ]

Genes GLIS2

Translocations implicated (Data extracted from papers in the Atlas)

 inv(16)(p13q24) CBFA2T3/GLIS2

External links

CBFA2T3 (16q24.3) GLIS2 (16p13.3)

CBFA2T3 (16q24.3) GLIS2 (16p13.3)

Mitelman databaseinv(16)(p13q24)
arrayMap (UZH-SIB Zurich)Topo ( C42) Morph ( 9861/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
Mitelman databaseCBFA2T3::GLIS2 [MCList]  CBFA2T3 (16q24.3) GLIS2 (16p13.3)
Mitelman databaseCBFA2T3::GLIS2 [MCList]  CBFA2T3 (16q24.3) GLIS2 (16p13.3)
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed

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