t(8;16)(p11;p13) KAT6A/CREBBP

2014-10-01   Thomas Smol , Thomas Smol 

1.Laboratoire de Génétique biologique, Histologie et BDR, CHU de Besançon, France.
2.Laboratoire de Cytogenetique, Hopital Saint-Antoine, Paris, France

Clinics and Pathology

Disease

Acute myeloid leukemia (AML) including AML-M4, AML-M5a/M5b; Treatment related AML (t-AML).

Note

In t-AML with t(8;16), patients often had a previous history of solid tumour ( ) or haematological diseases ( (CMML), lymphomas).

Phenotype stem cell origin

AML with t(8;16) may arise from an early stem cell with myeloid and monoblastic differentiation potential.

Epidemiology

Rare disease: a hundred and twenty cases have been reported in Mitelman database; (<1% of AML); found in children (median age at diagnosis: 1.2 years) and adults (median age at diagnosis: 59.4 years) with a female predominance (2/3).

Clinics

Disseminated intra vascular coagulation may be present; extramedullary infiltration; 20% of the cases could be therapy-related.
Atlas Image
The t(8;16) has been cloned and shown to fuse the MOZ (monocytic leukemia zinc finger) gene at 8p11.2 to the CBP (CREB binding protein) gene at 16p13.3. The MOZ gene has also been found to be involved in variant translocations t(8;19)(p11;q13) and t(8;22)(p11;q13) and inv(8)(p11q13) translocations associated with M5/M4 AML.This translocation is associated with AML M5/M4. In the majority of cases it is associated with features of hemophagocytosis by leukemic cells, particularly erythrophagocytosis - Text and iconography Courtesy Georges Flandrin 2001.

Cytology

Blast cells present a myelomonocytic stage of differentiation, and are characterized by a phenomenon of erythrophagocytosis with strong peroxidase and esterase activities. Immunophenotyping reveals CD4, CD14, CD13, CD33, CD56 and HLA-DR positives; CD34, CD117 and CD133 negatives.

Prognosis

The prognosis is poor. In published series, death of patients occurs in half of the cases during the first 10 months after diagnosis due to infections or bleeding; survival is often less than 1 year but spontaneous remission has occurred (at least) once.

Cytogenetics

Atlas Image
t(8;16)(p11;p13) : FISH with BAC KAT6A RP11-313J18 (8p11-21) probe (Amplitech) in red and BAC RP11-489O1 (16p13.11) probe (Amplitech) in green - Courtesy Thomas Smol and Marie-Agnès Collonge-Rame.

Additional anomalies

Sole anomaly in 53.3% of cases; in 23.3% of cases, single additional abnormality: +8 ,various; in 23.3% of cases: complex karyotype; rare chromosome 7 abnormalities, often in t-AML.

Variants

Complex variant t(8;16;V) may occur and has been described on rare occasions. 8p11 may have other partners: t(8;22)(p11;q13) which involve EP300 in 22q13, EP300 is a homologue of CREBBP with acetyltransferase activity; t(8;19)(p11;q13.3) which should involve LEUTX on 19q13 (found in one t-AML case); inv(8)(p11p13) which leads to MYST3- NCOA2 fusion; t(8;20)(p11;q13) leading to MYST3- NCOA3 fusion.

Genes Involved and Proteins

Gene name
KAT6A (MYST histone acetyltransferase (monocytic leukemia) 3
Location
8p11.21
Note
KAT6A is also known as MYST3, or MOZ (monocytic leukemia zinc finger).
Dna rna description
KAT6A gene is composed of 17 exons, with a MYST domain, located in exons 9-14, that remains intact in the t(8;16) translocations.
Protein description
KAT6A gene encodes for a nuclear protein with histone acetyltransferase (HAT) due to MYST domain, and transcriptional regulator activities.
Gene name
CREBBP (CREB binding protein)
Location
16p13.3
Note
CREBBP is also known as CBP.
Dna rna description
CREBBP is composed of 31 exons.
Protein description
The protein encoded shows intrinsic histone acetyltransferase activity and shares regions of very high sequence similarity with protein p300.

Result of the Chromosomal Anomaly

Atlas Image
Blue boxes represent exons of KAT6A gene and orange boxes represent exons of CREBBP gene (diagram is not to scale).

Description

5 KAT6A - 3 CREBBP or 5 CREBBP - 3 KAT6A.

Transcript

TRANSCRIPT Five KAT6A -CREBBP transcripts have been descripted: type I (KAT6A exon 16 - CREBBP exon 3); type II (KAT6A exon 16 - CREBBP exon 4); type III (KAT6A exon 17 - CREBBP exon 2 or 4); type IV (KAT6A exon 15 - CREBBP exon 4); type V (KAT6A exon 15 - CREBBP exon 5). Type I transcript is the most frequent fusion product. Reciprocal transcripts CREBBP- KAT6A: type I (CREBBP exon 2 - KAT6A exon 17); type IV (CREBBP exon 3 - KAT6A exon 16) are also found.
Atlas Image
H1/5: Histone H1/5-like; ZF: zinc finger domain; HAT: Histone Acetyltransferase; S: serine-rich domain; QP: glutamine and proline-rich domain; M: methionine-rich domain; RID: receptor-interacting domain; CH1-2-3: cysteine and histidine-rich domain; KIX: binding site of CREB; Bd: bromodomain; Q: glutamine-rich domain.

Description

The breakpoint for KAT6A is amino acid 1.013 or amino acid 1.117 (in the acidic domain). Fusion protein loses part of acidic domain in C-terminal. HAT domains in KAT6A and CREBBP are conserved.

Oncogenesis

t(8;16) AML are characterized by overexpression of HOXA9, HOXA10, and MEIS1; upregulation of RET and PRL; downregulation of CCND2, STAT5 and WT1. They share similarities with MLL-rearranged leukemias suggesting a partially common leukemogenic pathway.

Bibliography

Pubmed IDLast YearTitleAuthors
87828171996The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein.Borrow J et al
31849871988The 8p11 anomaly in "monoblastic" leukaemia.Brizard A et al
168495382006Gene expression profiling of acute myeloid leukemia with translocation t(8;16)(p11;p13) and MYST3-CREBBP rearrangement reveals a distinctive signature with a specific pattern of HOX gene expression.Camós M et al
244460902014The leucine twenty homeobox (LEUTX) gene, which lacks a histone acetyltransferase domain, is fused to KAT6A in therapy-related acute myeloid leukemia with t(8;19)(p11;q13).Chinen Y et al
239742012013Pediatric acute myeloid leukemia with t(8;16)(p11;p13), a distinct clinical and biological entity: a collaborative study by the International-Berlin-Frankfurt-Munster AML-study group.Coenen EA et al
230229872013Acute myeloid leukemia with translocation (8;16)(p11;p13) and MYST3-CREBBP rearrangement harbors a distinctive microRNA signature targeting RET proto-oncogene.Díaz-Beyá M et al
92906201997Spontaneous remission of congenital leukemia.Dinulos JG et al
185284282008Acute myeloid leukaemia with 8p11 (MYST3) rearrangement: an integrated cytologic, cytogenetic and molecular study by the groupe francophone de cytogénétique hématologique.Gervais C et al
191944662009AML with translocation t(8;16)(p11;p13) demonstrates unique cytomorphological, cytogenetic, molecular and prognostic features.Haferlach T et al
82460251993Therapy-related acute myeloid leukemia with t(8;21), inv(16), and t(8;16): a report on 25 cases and review of the literature.Quesnel B et al
151010472004Type I MOZ/CBP (MYST3/CREBBP) is the most common chimeric transcript in acute myeloid leukemia with t(8;16)(p11;p13) translocation.Rozman M et al
150851632004RT-PCR and FISH analysis of acute myeloid leukemia with t(8;16)(p11;p13) and chimeric MOZ and CBP transcripts: breakpoint cluster region and clinical implications.Schmidt HH et al
75961491995A distinct subtype of M4/M5 acute myeloblastic leukemia (AML) associated with t(8:16)(p11:p13), in a patient with the variant t(8:19)(p11:q13)--case report and review of the literature.Stark B et al
89072811996Translocation t(8;16)(p11;p13) in acute non-lymphocytic leukemia: report on two new cases and review of the literature.Velloso ER et al

Summary

Fusion gene

KAT6A/CREBBP KAT6A (8p11.21) CREBBP (16p13.3) M t(8;16)(p11;p13)|KAT6A/CREBBP KAT6A (8p11.21) CREBBP (16p13.3) TIC
Atlas Image
t(8;16)(p11;p13) G- banding (left) - Courtesy Thomas Smol and Marie-Agnès Collonge-Rame (top), Jean-Luc Lai (second row) and Charles D. Bangs (third and bottom row), R- banding (right) - Courtesy Thomas Smol and Marie-Agnès Collonge-Rame (top) and Jean-Luc Lai (second row), and ideogram (bottom right) - Courtesy Charles D. Bangs.

Citation

Thomas Smol ; Thomas Smol

t(8;16)(p11;p13) KAT6A/CREBBP

Atlas Genet Cytogenet Oncol Haematol. 2014-10-01

Online version: http://atlasgeneticsoncology.org/haematological/1018/t(8;16)(p11;p13)

Historical Card

1998-12-01 t(8;16)(p11;p13) KAT6A/CREBBP by  Christine Pérot,Christine Pérot 

Laboratoire de Génétique biologique, Histologie et BDR, CHU de Besançon, France.

1997-10-01 t(8;16)(p11;p13) KAT6A/CREBBP by  Jean-Loup Huret,Christine Pérot 

Laboratoire de Cytogenetique, Hopital Saint-Antoine, Paris, France

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