t(7;17)(q11;q21) GTF2I/RARA in APL

2014-11-01 Guang-Sen Zhang Affiliation

1.Department of Hematology/Institute of Molecular Hematology, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, 410011, P.R of China; E-mail: zgsllzy@163.com

Abstract

Review on t(7;17)(q11;q21) GTF2I/RARA in acute promyelocytic leukaemia, with data on clinics, and the genes involved.

Clinics and Pathology

Disease

variant acute promyelocytic leukemia with ATRA resistance

Phenotype stem cell origin

HLA-DR-, CD34-, CD13+, CD33+, CD64+.

Epidemiology

One case reported so far. A 35-year old male.

Clinics

The patient exhibited leukocytosis and coagulopathy.

Mophorlogy of GTF2I-RARA variant APL. Wright Giemsa staining. Image acquired at x1000 magnification.

Cytology

The cytoplasm was occupied by densely packed coarse granules. The nuclei were relatively regular. Auer rods and fagot cells were absent. MPO staining is strongly positive.

Treatment

ATRA in combination with anthracycline-based chemotherapy did not induce remission. Neither are conventional chemotherapy and ATRA in combination with arsenics. No morphology differentiation of blast cells was seen after ATRA treatment.

Evolution

No remission was obtained after ATRA and conventional chemotherapy. The patient died of intracranial hemorrhage on day 143 without remission.

Prognosis

Bad.

Cytogenetics

Note

Cryptic translocation. FISH studies are needed to uncover the rearrangment.

Metaphase fluorescence in situ hybridization (FISH). On the left, PML-RARA dual colour, dual-fusion translocation probes found RARA rearrangement. The RARA signals are shown in red, while PML signals are shown in green. Intact RARA and PML are shown as (r) and (p), while the split RARA signals are indicated as (s).In the middle, probes specific for the chromosome 7 centromere (GLP D7S486 probes, green) and 7q31 (CSP7 probes, red) confirmed the deletion of the long arm of one chromosome 7. On the right, the combined application of chromosome 7 probes and PML-RARA probes found that one split RARA was translocated to the truncated long arm of chromosome 7. Signal detection was carried out on metaphases according to the manufacturers protocols (Jinpujia, Beijing, China).

Genes Involved and Proteins

Gene name

GTF2I (general transcription factor IIi)

Location

7q11.23

Note

General transcription factor IIi

Protein description

GTF2I is a ubiquitously expressed phosphoprotein with broad roles in transcription and signal transduction involving growth factor signalling, cell cycle regulation, and transforming growth factor, beta 1(TGFB1) signalling, ER stress response pathway, calcium signalling, and immune signalling (Roy, 2012).

Gene name

RARA (Retinoic acid receptor, alpha)

Location

17q21.2

Note

Retinoic acid receptor alpha

Protein description

RARA is a nuclear retinoic acid receptor that regulates transcription in a ligand-dependent manner. This gene has been implicated in regulation of hemopoietic cells differentiation.

Result of the Chromosomal Anomaly

Note

In-frame fusion of exon 6 of GTF2I to exon 3 of RARA

Transcript

5GTF2I-3RARA. No reciprocal 5RARA-3GTF2I.

Detection protocole

Reverse transcript polymerase chain reaction.

Schematic diagram of RARA, GTF2I and GTF2I-RARA fusion protein. A black line indicates the break point. DBD, DNA-binding domain; LBD +DD, ligand-binding domain and dimerization domain; LZ, leucine zipper; NLS, nuclear localization signal; BR, basic region; R1-R6, I-repeat domains.

Description

The fusion transcript encodes a 598 amino acids chimera containing the 195 amino-terminal amino acids of GTF2I, including the N-terminal leucine zipper and the first I-repeat domain, and 403 carboxyl-terminal amino acids of RARA, including the DNA and ligand binding domains.

Expression localisation

Two patterns of GTF2I-RARA localization were observed: diffuse nuclear distribution with a micropunctate pattern, and aggregation in the cytoplasm as macrogranules.

Oncogenesis

GTF2I-RARA chimera possesses common features of APL related fusion proteins: the same RARA portion, the ability to self-associate, dominant-negative regulation of the retinoic acid response element, and aberrant subcellular localization.

Highly cited references

Pubmed ID	Year	Title	Citations
25284716	2015	GTF2I-RARA is a novel fusion transcript in a t(7;17) variant of acute promyelocytic leukaemia with clinical resistance to retinoic acid.	21
32907914	2021	Gene of the month: GTF2I.	4
30992691	2019	RNF8 is responsible for ATRA resistance in variant acute promyelocytic leukemia with GTF2I/RARA fusion, and inhibition of the ubiquitin-proteasome pathway contributes to the reversion of ATRA resistance.	4

Article Bibliography

Pubmed ID	Last Year	Title	Authors
25284716	2015	GTF2I-RARA is a novel fusion transcript in a t(7;17) variant of acute promyelocytic leukaemia with clinical resistance to retinoic acid.	Li J et al
22037610	2012	Biochemistry and biology of the inducible multifunctional transcription factor TFII-I: 10 years later.	Roy AL et al

Summary

G-banding karyotype of del(7q). No distinct chromosome tranlocation.

Citation

Guang-Sen Zhang

t(7;17)(q11;q21) GTF2I/RARA in APL

Atlas Genet Cytogenet Oncol Haematol. 2014-11-01

Online version: http://atlasgeneticsoncology.org/haematological/1711/meetings/gene-fusions-explorer/deep-insight-explorer/