t(11;17)(q23;q21) ZBTB16/RARA

1998-04-01   Franck Viguié 

Clinics and Pathology

Disease

specifically observed in acute promyelocytic leukemia (APL), or M3 AML; in the vast majority of cases, M3 AML is characterized by a t(15;17)(q25;q21); the t(11;17) represents a rare variant translocationwith characteristic clinicopathologic features concerning presentation, response to treatment with all-trans retinoic acid (ATRA) and prognosis.

Phenotype stem cell origin

promyelocytic (M3) acute leukaemia; a number of patients express an unusual morphologic spectrum intermediate between M2 and M3 AML.

Epidemiology

less than 1% of morphologic M3 AML.

Clinics

high incidence at diagnosis of disseminated intravascular coagulation; poor response to ATRA at induction therapy, in contrast with the classical M3 AML with t(15;17).

Cytology

high rate of normal or dystrophic promyelocytes in peripheralblood and in bone marrow; no intracytoplasmic Auer rods; myeloperoxydasereaction positive; immunocytochemical detection with an anti-PLZF shows adistinct punctate nuclear distribution of the protein, suggesting itscompartmentalization in the nucleus.
Atlas Image
In patients with t(11;17)(q23;q21), t(5;17)(q35;q21), and t(11;17)(q13;q21) where RARa is fused to the PLZF (promyelocytic leukemia zinc finger), NPM (nucleophosmin) and NuMA (nuclear mitotic apparatus) genes respectively, chromosome 17 and RARa but not PML are involved. Patients were initially reported as having M3 morphology. Interestingly, the t(11;17)(q23;q21) PLZF/RARa subgroup showed a clearly morphological differences with predominance of cells with regular nuclei, many granules, usually no Auer rods, increased number of pseudo Pelger-Huet cells and a strong MPO activity. These particular characteristics could allow the definition of a separate morphological entity among APL. Patients with t(5;17)(q35;q21) are too rares to draw any morphological correlation - Text and iconography Courtesy Georges Flandrin 2001.

Prognosis

distinctly worse prognosis than M3 AML with t(15;17), mainlybecause the patients fail to respond to the maturation effect of ATRA.

Cytogenetics

Cytogenetics molecular

fusion of distal PLZF probe with RARa on 17q21.

Additional anomalies

no recurrent additional anomaly are known.

Variants

3 related translocations observed in M3 AML; the first is the common translocation (15;17) and the two others are extremelly rare; all these translocations involve a breakpoint at 17q21, in RARa, which fuses with different partners:1- t(15;17)(q22;q21), fusion with PML in 15q22;2- t(5;17)(q32;q12), fusion with NPM1 in 5q32, encoding for a RNA processing protein;3- t(11;17)(q13;q21), fusion with NUMA in 11q13, involved in the control of mitosis.

Genes Involved and Proteins

Gene name
ZBTB16 (zinc finger and BTB domain containing 16)
Location
11q23.2
Dna rna description
Krüppel-like zinc finger gene.
Protein description
transcription factor associated with myeloid maturation.
Gene name
RARA (Retinoic acid receptor, alpha)
Location
17q21.2
Protein description
nuclear receptor with DNA binding and transcriptional properties.

Result of the Chromosomal Anomaly

Description

the translocation involves a breakpoint in the zinc fingerregion of PLZF, with fusion of two zinc fingers to the RARa B region toform a 5 PLZF - 3 RARa fusion gene; the reciprocal 5 RARa - 3 PLZF genefuses seven zinc fingers to the RARa region; RARas breakpoint occurs in1- as a result of thealternative splicing of PLZF gene, two forms of PLZF-RARa protein can be detected: , b) PLZF(B)-RARa (858 amino acids; 93 kDa) differing from form A by the inclusion of a 123 amino acid prolin rich segment of PLZF; PLZF-RARa protein is an abnormal retinoic acid receptor with reduced and modified DNA-binding and transcriptional activities.
 , 2- Two forms of RARa-PLZF protein are also detected, due to involvement of alternative promoters of the RARa gene: RARa(A1)-PLZF (277 amino acids; 31 kDa) and RARa(A2)-PLZF (274 amino acids; 31 kDa), composed of A1 or A2 transcriptional activation domain of RARa linked to the seven C-terminal zinc fingers of PLZF.

Transcript

both 5 PLZF -3 RARa and 5 RARa - 3 PLZF transcripts aredetected by RT-PCR, and both fusion partners would be implicated inleukemogenesis; four chimeric transcripts are produced, due to alternativesplicing of PLZF gene and to transcription of either A1 or A2 domain ofRARa gene

Description

a) PLZF(A)-RARa (735 amino acids; 81 kDa) composed of the N-term part of PLZF including POZ domain and two of the nine zinc fingers, fused to the DNA and ligand binding domains of RARa

Bibliography

Pubmed IDLast YearTitleAuthors
88190701996Variant and masked translocations in acute promyelocytic leukemia.Brunel V et al
83875451993Rearrangements of the retinoic acid receptor alpha and promyelocytic leukemia zinc finger genes resulting from t(11;17)(q23;q21) in a patient with acute promyelocytic leukemia.Chen SJ et al
83845531993Fusion between a novel Krüppel-like zinc finger gene and the retinoic acid receptor-alpha locus due to a variant t(11;17) translocation associated with acute promyelocytic leukaemia.Chen Z et al
93897041997Characterization of cryptic rearrangements and variant translocations in acute promyelocytic leukemia.Grimwade D et al
78492961995Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17).Licht JD et al
27907651989A new variant translocation 11;17 in a patient with acute promyelocytic leukemia together with t(7;12).Najfeld V et al
89521641996PML, PLZF and NPM genes in the molecular pathogenesis of acute promyelocytic leukemia.Pandolfi PP et al

Summary

Fusion gene

ZBTB16/RARA ZBTB16 (11q23.2) RARA (17q21.2) M ins(11;17)(q23;q21q21) t(11;17)(q23;q21) t(15;17)(q22;q21) t(5;17)(q35;q21)|ZBTB16/RARA ZBTB16 (11q23.2) RARA (17q21.2) TIC
Atlas Image
t(11;17)(q23;q21) G- banding - Courtesy Diane H. Norback, Eric B. Johnson, Sara Morrison-Delap UW Cytogenetic Services .

Citation

Franck Viguié

t(11;17)(q23;q21) ZBTB16/RARA

Atlas Genet Cytogenet Oncol Haematol. 1998-04-01

Online version: http://atlasgeneticsoncology.org/haematological/1028/t(11;17)(q23;q21)-zbtb16-rara

External Links