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

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).

Genes Involved and Proteins

Gene name
GLIS2 (GLIS family zinc finger 2)
Location
16p13.3
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)
Location
16q24.3
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

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).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).

Highly cited references

Pubmed IDYearTitleCitations
334393822021Acute Myeloid Leukemia in Children: Emerging Paradigms in Genetics and New Approaches to Therapy.101
261869392015The biology of pediatric acute megakaryoblastic leukemia.98
370199722023Etiology of oncogenic fusions in 5,190 childhood cancers and its clinical and therapeutic implication.71
377296152024CBFA2T3::GLIS2 pediatric acute megakaryoblastic leukemia is sensitive to BCL-XL inhibition by navitoclax and DT2216.69
231535402012An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia.69
393848142024CBFA2T3-GLIS2 mediates transcriptional regulation of developmental pathways through a gene regulatory network.56
367895452023Pathologic, cytogenetic, and molecular features of acute myeloid leukemia with megakaryocytic differentiation: A report from the Children's Oncology Group.51
317190492020Comprehensive Transcriptome Profiling of Cryptic CBFA2T3-GLIS2 Fusion-Positive AML Defines Novel Therapeutic Options: A COG and TARGET Pediatric AML Study.50
380869452024Panel-based RNA fusion sequencing improves diagnostics of pediatric acute myeloid leukemia.49
241275502013DHH-RHEBL1 fusion transcript: a novel recurrent feature in the new landscape of pediatric CBFA2T3-GLIS2-positive acute myeloid leukemia.48
230456052012Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models.48
281744172017AMKL chimeric transcription factors are potent inducers of leukemia.45
305922962019CBFA2T3-GLIS2-positive acute myeloid leukaemia. A peculiar paediatric entity.44
361366002022CBFA2T3-GLIS2 model of pediatric acute megakaryoblastic leukemia identifies FOLR1 as a CAR T cell target.42
281127372017Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes.41
271144622016Recurrent abnormalities can be used for risk group stratification in pediatric AMKL: a retrospective intergroup study.39
398669462025Clinical, immunophenotypic, and genomic findings of acute myeloid leukemia with RAM immunophenotype: Comparison with other CD56-positive acute leukemias.35
387860532024CBFA2T3 Is PPARA Sensitive and Attenuates Fasting-Induced Lipid Accumulation in Mouse Liver.34
338114452021CD56, HLA-DR, and CD45 recognize a subtype of childhood AML harboring CBFA2T3-GLIS2 fusion transcript.27
383158962024Clinical Analysis of Pediatric Acute Megakaryocytic Leukemia With CBFA2T3-GLIS2 Fusion Gene.26
352940812022Acute megakaryoblastic leukemia with trisomy 3 and CBFA2T3::GLIS2: A case report.24
338329212021Clinical impact of genomic characterization of 15 patients with acute megakaryoblastic leukemia-related malignancies.24
360037952022Revealing the intratumoral heterogeneity of non-DS acute megakaryoblastic leukemia in single-cell resolution.22
270945032016Clinical Courses of Two Pediatric Patients with Acute Megakaryoblastic Leukemia Harboring the CBFA2T3-GLIS2 Fusion Gene.18
376018752023CBFA2T3::GLIS2-positive acute leukemia with RAM and mixed T/megakaryocytic phenotype.16
359270232022Detection of a GLIS3 fusion in an infant with AML refractory to chemotherapy.14
312945072020Deciphering the Significance of CD56 Expression in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group.12
281093232017Hh/Gli antagonist in acute myeloid leukemia with CBFA2T3-GLIS2 fusion gene.10
349767212022Acute myeloid leukemia with RAM immunophenotype presenting with extensive mesenteric and retroperitoneal lymphadenopathy: A case report and review of the literature.8
377163552023CBFA2T3-GLIS2-dependent pediatric acute megakaryoblastic leukemia is driven by GLIS2 and sensitive to navitoclax.0
391454562024CBFA2T3-GLIS2 model of pediatric acute megakaryoblastic leukemia identifies FOLR1 as a CAR T cell target.0
376933712023Chromatin Profiling of CBFA2T3-GLIS2 AMLs Identifies Key Transcription Factor Dependencies and BRG1 Inhibition as a Novel Therapeutic Strategy.0
394181282024Myeloid sarcomas with CBFA2T3 : GLIS2 fusion: clinicopathologic characterization of 4 cases mimicking small round cell tumors.0
280631902017Prognostic impact of specific molecular profiles in pediatric acute megakaryoblastic leukemia in non-Down syndrome.0
363463682023Frequent detection of CBFA2T3::GLIS2 fusion and RAM-phenotype in pediatric non-Down syndrome acute megakaryoblastic leukemia: a possible novel relationship with aberrant cytoplasmic CD3 expression.0
234075492013CBFA2T3-GLIS2 fusion transcript is a novel common feature in pediatric, cytogenetically normal AML, not restricted to FAB M7 subtype.0
317921232019Oncogenic Drivers and Development.0
375483332023BCR-ABL1 co-occurring with CBFA2T3-GLIS2 and RAM immunophenotype in a non-Down syndrome infant with acute megakaryoblastic leukemia.0
317362542020CBFA2T3-GLIS2-positive acute megakaryoblastic leukemia in a patient with Down syndrome.0
399764312025A Rare Case of Acute Leukemia With CBFA2T3::GLIS2 Fusion Exhibiting a T/Megakaryocyte Mixed Phenotype.0
386392012024Immunophenotypic clustering in paediatric acute myeloid leukaemia.0
310923682019The changing scenario of non-Down syndrome acute megakaryoblastic leukemia in children.0
370785112023Acute myeloid leukemia with RAM immunophenotype: A new underdiagnosed entity.0
342601402021Azacitidine and venetoclax for post-transplant relapse in a case of CBFA2T3/GLIS2 childhood acute myeloid leukaemia.0
290438652018A pediatric case of acute megakaryocytic leukemia with double chimeric transcripts of CBFA2T3-GLIS2 and DHH-RHEBL1.0
303055342018[Genetic aberrations and new treatment strategies for pediatric acute myeloid leukemia].0
389531492024High DOCK1 expression identifies a distinct prognostic subgroup of pediatric acute myeloid leukemia: Results of the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 trial.0
308423872019[Prognostic significance of chimeric fusion gene analysis in pediatric acute megakaryoblastic leukemia].0
316124662020Patients aged less than 3 years with acute myeloid leukaemia characterize a molecularly and clinically distinct subgroup.0
397816102025Novel classification system and high-risk categories of pediatric acute myeloid leukemia.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
398088032025Precision Medicine for High-Risk Gene Fusions in Paediatric AML: a focus on KMT2A, NUP98, and GLIS2 Rearrangements.0
235315172013NUP98/JARID1A is a novel recurrent abnormality in pediatric acute megakaryoblastic leukemia with a distinct HOX gene expression pattern.0
294275262018NUP98-BPTF gene fusion identified in primary refractory acute megakaryoblastic leukemia of infancy.0

Article Bibliography

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

Summary

Fusion gene

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

Citation

Jean-Loup Huret

inv(16)(p13q24) CBFA2T3/GLIS2

Atlas Genet Cytogenet Oncol Haematol. 2012-11-01

Online version: http://atlasgeneticsoncology.org/haematological/1624/inv(16)(p13q24)