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

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

Identity

t(11;17)(q23;q21) G- banding - Courtesy Diane H. Norback, Eric B. Johnson, Sara Morrison-Delap UW Cytogenetic Services .

Clinics and Pathology

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

Phenotype / cell stem 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 ANLL.

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

Cytology high rate of normal or dystrophic promyelocytes in peripheral blood and in bone marrow; no intracytoplasmic Auer rods; myeloperoxydase reaction positive; immunocytochemical detection with an anti-PLZF shows a distinct punctate nuclear distribution of the protein, suggesting its compartmentalization in the nucleus.

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 ANLL with t(15;17), mainly because 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 ANLL; 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 PLZF

Location 11q24

Dna / Rna Krüppel-like zinc finger gene.

Protein transcription factor associated with myeloid maturation.

Gene Name RARa

Location 17q21

Protein nuclear receptor with DNA binding and transcriptional properties.

Result of the chromosomal anomaly

Hybrid gene
Description the translocation involves a breakpoint in the zinc finger region of PLZF, with fusion of two zinc fingers to the RARa B region to form a 5' PLZF - 3' RARa fusion gene; the reciprocal 5' RARa - 3' PLZF gene fuses seven zinc fingers to the RARa region; RARa's breakpoint occurs in intron 2, as is in classical t(15;17)

Transcript both 5' PLZF -3' RARa and 5' RARa - 3' PLZF transcripts are detected by RT-PCR, and both fusion partners would be implicated in leukemogenesis; four chimeric transcripts are produced, due to alternative splicing of PLZF gene and to transcription of either A1 or A2 domain of RARa gene

Fusion Protein
Description 1- as a result of thealternative splicing of PLZF gene, two forms of PLZF-RARa protein can be detected: 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 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.

External links

Other database t(11;17)(q23;q21) ZBTB16/RARA Mitelman database (CGAP - NCBI)

Other database	t(11;17)(q23;q21) ZBTB16/RARA	Mitelman database (CGAP - NCBI)

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

Genes GATA2 NUMA1 ZBTB16 RARA

Bibliography

A new variant translocation 11;17 in a patient with acute promyelocytic leukemia together with t(7;12).

Najfeld V, Scalise A, Troy K

Cancer genetics and cytogenetics. 1989 ; 43 (1) : 103-108.

PMID 2790765

Rearrangements 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, Zelent A, Tong JH, Yu HQ, Wang ZY, Derrˆ© J, Berger R, Waxman S, Chen Z

The Journal of clinical investigation. 1993 ; 91 (5) : 2260-2267.

PMID 8387545

Fusion between a novel Krˆºppel-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, Brand NJ, Chen A, Chen SJ, Tong JH, Wang ZY, Waxman S, Zelent A

The EMBO journal. 1993 ; 12 (3) : 1161-1167.

PMID 8384553

Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17).

Licht JD, Chomienne C, Goy A, Chen A, Scott AA, Head DR, Michaux JL, Wu Y, DeBlasio A, Miller WH Jr

Blood. 1995 ; 85 (4) : 1083-1094.

PMID 7849296

Variant and masked translocations in acute promyelocytic leukemia.

Brunel V, Lafage-Pochitaloff M, Alcalay M, Pelicci PG, Birg F

Leukemia & lymphoma. 1996 ; 22 (3-4) : 221-228.

PMID 8819070

PML, PLZF and NPM genes in the molecular pathogenesis of acute promyelocytic leukemia.

Pandolfi PP

Haematologica. 1996 ; 81 (5) : 472-482.

PMID 8952164

Characterization of cryptic rearrangements and variant translocations in acute promyelocytic leukemia.

Grimwade D, Gorman P, Duprez E, Howe K, Langabeer S, Oliver F, Walker H, Culligan D, Waters J, Pomfret M, Goldstone A, Burnett A, Freemont P, Sheer D, Solomon E

Blood. 1997 ; 90 (12) : 4876-4885.

PMID 9389704

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Last year articles automatic search in PubMed

Contributor(s)

Written 04-1998 Franck Viguié

Citation

This paper should be referenced as such :
Viguié F . t(11;17)(q23;q21) ZBTB16/RARA. Atlas Genet Cytogenet Oncol Haematol. April 1998 .

URL : http://AtlasGeneticsOncology.org/Anomalies/t1117ID1028.html

The various updated versions of this paper are referenced and archived by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/37441/1/04-1998-t1117ID1028.pdf [ Bibliographic record ]

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indexed on : Fri Apr 18 14:12:13 CEST 2014

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Disease	specifically observed in acute promyelocytic leukemia (APL), or M3 ANLL; in the vast majority of cases, M3 ANLL is characterized by a t(15;17)(q25;q21); the t(11;17) represents a rare variant translocation with characteristic clinicopathologic features concerning presentation, response to treatment with all-trans retinoic acid (ATRA) and prognosis.
Phenotype / cell stem 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 ANLL.
Clinics	high incidence at diagnosis of disseminated intravascular coagulation; poor response to ATRA at induction therapy, in contrast with the classical M3 ANLL with t(15;17).
Cytology	high rate of normal or dystrophic promyelocytes in peripheral blood and in bone marrow; no intracytoplasmic Auer rods; myeloperoxydase reaction positive; immunocytochemical detection with an anti-PLZF shows a distinct punctate nuclear distribution of the protein, suggesting its compartmentalization in the nucleus.


	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 ANLL with t(15;17), mainly because the patients fail to respond to the maturation effect of ATRA.

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 ANLL; 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.

Gene Name	PLZF
Location	11q24
Dna / Rna	Krüppel-like zinc finger gene.
Protein	transcription factor associated with myeloid maturation.

Gene Name	RARa
Location	17q21
Protein	nuclear receptor with DNA binding and transcriptional properties.

Description	the translocation involves a breakpoint in the zinc finger region of PLZF, with fusion of two zinc fingers to the RARa B region to form a 5' PLZF - 3' RARa fusion gene; the reciprocal 5' RARa - 3' PLZF gene fuses seven zinc fingers to the RARa region; RARa's breakpoint occurs in intron 2, as is in classical t(15;17)
Transcript	both 5' PLZF -3' RARa and 5' RARa - 3' PLZF transcripts are detected by RT-PCR, and both fusion partners would be implicated in leukemogenesis; four chimeric transcripts are produced, due to alternative splicing of PLZF gene and to transcription of either A1 or A2 domain of RARa gene

REVIEW articles	automatic search in PubMed
Last year articles	automatic search in PubMed