inv(16)(p13q24) CBFA2T3/GLIS2

2012-11-01   Jean-Loup Huret 

1.Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

Clinics and Pathology


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).


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.


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).

Genes Involved and Proteins

Gene name
GLIS2 (GLIS family zinc finger 2)
Protein description
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 name
CBFA2T3 (core-binding factor, runt domain, alpha subunit 2; translocated to, 3)
Protein description
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


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).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.


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).

Highly cited references

Pubmed IDYearTitleCitations
231535402012An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia.93
281127372017Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes.61
235315172013NUP98/JARID1A is a novel recurrent abnormality in pediatric acute megakaryoblastic leukemia with a distinct HOX gene expression pattern.58
234075492013CBFA2T3-GLIS2 fusion transcript is a novel common feature in pediatric, cytogenetically normal AML, not restricted to FAB M7 subtype.56
261869392015The biology of pediatric acute megakaryoblastic leukemia.46
230456052012Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models.38
271144622016Recurrent abnormalities can be used for risk group stratification in pediatric AMKL: a retrospective intergroup study.33
280631902017Prognostic impact of specific molecular profiles in pediatric acute megakaryoblastic leukemia in non-Down syndrome.18
281093232017Hh/Gli antagonist in acute myeloid leukemia with CBFA2T3-GLIS2 fusion gene.17
281744172017AMKL chimeric transcription factors are potent inducers of leukemia.16
317190492020Comprehensive Transcriptome Profiling of Cryptic CBFA2T3-GLIS2 Fusion-Positive AML Defines Novel Therapeutic Options: A COG and TARGET Pediatric AML Study.13
305922962019CBFA2T3-GLIS2-positive acute myeloid leukaemia. A peculiar paediatric entity.13
241275502013DHH-RHEBL1 fusion transcript: a novel recurrent feature in the new landscape of pediatric CBFA2T3-GLIS2-positive acute myeloid leukemia.13
316124662020Patients aged less than 3 years with acute myeloid leukaemia characterize a molecularly and clinically distinct subgroup.10
334393822021Acute Myeloid Leukemia in Children: Emerging Paradigms in Genetics and New Approaches to Therapy.7
312945072020Deciphering the Significance of CD56 Expression in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group.7
294275262018NUP98-BPTF gene fusion identified in primary refractory acute megakaryoblastic leukemia of infancy.7
310923682019The changing scenario of non-Down syndrome acute megakaryoblastic leukemia in children.4
338114452021CD56, HLA-DR, and CD45 recognize a subtype of childhood AML harboring CBFA2T3-GLIS2 fusion transcript.3
270945032016Clinical Courses of Two Pediatric Patients with Acute Megakaryoblastic Leukemia Harboring the CBFA2T3-GLIS2 Fusion Gene.3
338329212021Clinical impact of genomic characterization of 15 patients with acute megakaryoblastic leukemia-related malignancies.1
290438652018A pediatric case of acute megakaryocytic leukemia with double chimeric transcripts of CBFA2T3-GLIS2 and DHH-RHEBL1.1
360037952022Revealing the intratumoral heterogeneity of non-DS acute megakaryoblastic leukemia in single-cell resolution.0
342601402021Azacitidine and venetoclax for post-transplant relapse in a case of CBFA2T3/GLIS2 childhood acute myeloid leukaemia.0
359270232022Detection of a GLIS3 fusion in an infant with AML refractory to chemotherapy.0
352940812022Acute megakaryoblastic leukemia with trisomy 3 and CBFA2T3::GLIS2: A case report.0
349767212022Acute myeloid leukemia with RAM immunophenotype presenting with extensive mesenteric and retroperitoneal lymphadenopathy: A case report and review of the literature.0
328658822021Utility of CD36 as a novel addition to the immunophenotypic signature of RAM-phenotype acute myeloid leukemia and study of its clinicopathological characteristics.0
317362542020CBFA2T3-GLIS2-positive acute megakaryoblastic leukemia in a patient with Down syndrome.0
317921232019Oncogenic Drivers and Development.0
303055342018[Genetic aberrations and new treatment strategies for pediatric acute myeloid leukemia].0
308423872019[Prognostic significance of chimeric fusion gene analysis in pediatric acute megakaryoblastic leukemia].0


Pubmed IDLast YearTitleAuthors
231535402012An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia.Gruber TA et al
201163762010CBFA2T3-ZNF651, like CBFA2T3-ZNF652, functions as a transcriptional corepressor complex.Kumar R et al
223913032012Gli-similar proteins: their mechanisms of action, physiological functions, and roles in disease.Lichti-Kaiser K et al
230456052012Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models.Thiollier C et al


Fusion gene

CBFA2T3/GLIS2 CBFA2T3 (16q24.3) GLIS2 (16p13.3) M|CBFA2T3/GLIS2 CBFA2T3 (16q24.3) GLIS2 (16p13.3) M inv(16)(p13q24)


Jean-Loup Huret

inv(16)(p13q24) CBFA2T3/GLIS2

Atlas Genet Cytogenet Oncol Haematol. 2012-11-01

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