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

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

Written	1998-04	Franck Viguié
		Laboratoire de Cytogenetique - Service d'Hematologie Biologique, Hopital Hotel-Dieu - 75181 Paris Cedex 04, France

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Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS

ICD-Morpho 9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS

Atlas_Id 1028

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 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 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 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 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 AML 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 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 Krüppel-like zinc finger gene.

Protein transcription factor associated with myeloid maturation.

Gene Name RARA (Retinoic acid receptor, alpha)

Location 17q21.2

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.

Bibliography

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

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, Derré J, Berger R, Waxman S, Chen Z

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

PMID 8387545

Fusion 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, Brand NJ, Chen A, Chen SJ, Tong JH, Wang ZY, Waxman S, Zelent A

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

PMID 8384553

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

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

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

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

Pandolfi PP

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

PMID 8952164

Citation

This paper should be referenced as such :

Viguié, F

t(11;17)(q23;q21)

Atlas Genet Cytogenet Oncol Haematol. 1998;2(3):97-99.

Free journal version : [ pdf ] [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Anomalies/t1117ID1028.html

Other genes implicated (Data extracted from papers in the Atlas) [ 6 ]

Genes CCNA1 GATA2 IRF1 NUMA1 ZBTB16 RARA

Translocations implicated (Data extracted from papers in the Atlas)

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

External links

ZBTB16 (11q23.2) RARA (17q21.2)
ZBTB16 (11q23.2) RARA (17q21.2)
Mitelman database t(11;17)(q23;q21) [Case List]    t(11;17)(q23;q21) [Transloc-MCList] ZBTB16/RARA [Fusion-MCList]
arrayMap (UZH-SIB Zurich) Topo ( C42) Morph ( 9861/3) - [auto + random 100 samples .. if exist ] [tabulated segments]

Mitelman database ZBTB16/RARA [MCList]  ZBTB16 (11q23.2) RARA (17q21.2)

TICdb ZBTB16/RARA  ZBTB16 (11q23.2) RARA (17q21.2)

REVIEW articles automatic search in PubMed

Last year articles automatic search in PubMed

All articles automatic search in PubMed

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ICD-Topo	C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho	9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS
Atlas_Id	1028


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

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 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 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 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 AML 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 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.

Gene Name	ZBTB16 (zinc finger and BTB domain containing 16)
Location	11q23.2
Dna / Rna	Krüppel-like zinc finger gene.
Protein	transcription factor associated with myeloid maturation.

Gene Name	RARA (Retinoic acid receptor, alpha)
Location	17q21.2
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

Mitelman database	t(11;17)(q23;q21) [Case List] t(11;17)(q23;q21) [Transloc-MCList] ZBTB16/RARA [Fusion-MCList]
arrayMap (UZH-SIB Zurich)	Topo ( C42) Morph ( 9861/3) - [auto + random 100 samples .. if exist ] [tabulated segments]

Mitelman database	ZBTB16/RARA [MCList] ZBTB16 (11q23.2) RARA (17q21.2)
TICdb	ZBTB16/RARA ZBTB16 (11q23.2) RARA (17q21.2)

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