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

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

Written

This article is an update of :

	2014-10	Thomas Smol, Marie-Agnès Collonge-Rame
		Laboratoire de Cytogenetique, Hopital Saint-Antoine, Paris, France

	1998-12	Christine Pérot, Jean-Loup Huret
		Laboratoire de Cytogenetique, Hopital Saint-Antoine, Paris, France

	1997-10	Christine Pérot, Jean-Loup Huret
		-

(Note : for Links provided by Atlas : click)

Identity

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

ICD-Morpho 9837/3 T lymphoblastic leukaemia/lymphoma

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

Atlas_Id 1018

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.

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 / cell stem 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.

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.

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.

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

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 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 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 CREBBP is composed of 31 exons.

Protein The protein encoded shows intrinsic histone acetyltransferase activity and shares regions of very high sequence similarity with protein p300.

Result of the chromosomal anomaly

Hybrid gene
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.

Fusion Protein

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

The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein.

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The 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).

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Blood. 2013; 122(15): 2704-13.

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Acute myeloid leukemia with translocation t(8;16)(p11;p13) and MYST3-CREBBP rearrangement harbors a distinctive microRNA signature targeting RET proto-oncogene.

Dèaz-Beyá M, Navarro A, Ferrer G, Dèaz T, Gel B, Camós M, Pratcorona M, Torrebadell M, Rozman M, Colomer D, Monzo M, Esteve J.

Leukemia. 2013; 27(3): 595-603.

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Spontaneous remission of congenital leukemia.

Dinulos JG, Hawkins DS, Clark BS, Francis JS

The Journal of pediatrics. 1997 ; 131 (2) : 300-303.

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Acute myeloid leukaemia with 8p11 (MYST3) rearrangement: an integrated cytologic, cytogenetic and molecular study by the groupe francophone de cytogénétique hématologique.

Gervais C, Murati A, Helias C, Struski S, Eischen A, Lippert E, Tigaud I, Penther D, Bastard C, Mugneret F, Poppe B, Speleman F, Talmant P, VanDen Akker J, Baranger L, Barin C, Luquet I, Nadal N, Nguyen-Khac F, Maarek O, Herens C, Sainty D, Flandrin G, Birnbaum D, Mozziconacci MJ, Lessard M; Groupe Français de Cytogénétique Hématologique (GFCH).

Leukemia. 2008; 22(8): 1567-75.

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AML with translocation t(8;16)(p11;p13) demonstrates unique cytomorphological, cytogenetic, molecular and prognostic features.

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Therapy-related acute myeloid leukemia with t(8;21), inv(16), and t(8;16): a report on 25 cases and review of the literature.

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Type I MOZ/CBP (MYST3/CREBBP) is the most common chimeric transcript in acute myeloid leukemia with t(8;16)(p11;p13) translocation.

Rozman M, Camós M, Colomer D, Villamor N, Esteve J, Costa D, Carrió A, Aymerich M, Aguilar JL, Domingo A, Solé F, Gomis F, Florensa L, Montserrat E, Campo E.

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Citation

This paper should be referenced as such :

Smol T, Collonge-Rame MA

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

Atlas Genet Cytogenet Oncol Haematol. in press

On line version : http://AtlasGeneticsOncology.org/Anomalies/t0816ID1018.html

History of this paper:

Pérot, C, Huret, JL. t(8;16)(p11;p13). Atlas Genet Cytogenet Oncol Haematol. 1997;1(2):79-80.

http://documents.irevues.inist.fr/bitstream/handle/2042/32062/10-1997-t0816ID1018.pdf

Pérot, C, Huret, JL. t(8;16)(p11;p13). Atlas Genet Cytogenet Oncol Haematol. 1999;3(1):36-38.

http://documents.irevues.inist.fr/bitstream/handle/2042/37488/12-1998-t0816.pdf

Thomas Smol, Marie-Agns Collonge-Rame. t(8;16)(p11;p13) KAT6A/CREBBP. Atlas Genet Cytogenet Oncol Haematol. 2015;19(7):476-480.

http://documents.irevues.inist.fr/bitstream/handle/2042/62192/10-2014-t0816ID1018.pdf

Other genes implicated (Data extracted from papers in the Atlas) [ 4 ]

Genes CREBBP MYH11 KAT6A KAT6B

Translocations implicated (Data extracted from papers in the Atlas)

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

External links

KAT6A (8p11.21) CREBBP (16p13.3)
KAT6A (8p11.21) CREBBP (16p13.3)
Mitelman database t(8;16)(p11;p13)
arrayMap (UZH-SIB Zurich) Topo ( C42) Morph ( 9837/3) - [auto + random 100 samples .. if exist ] [tabulated segments]

arrayMap (UZH-SIB Zurich) Topo ( C42) Morph ( 9861/3) - [auto + random 100 samples .. if exist ] [tabulated segments]

Mitelman database KAT6A/CREBBP [MCList] KAT6A (8p11.21) CREBBP (16p13.3)

TICdb KAT6A/CREBBP KAT6A (8p11.21) CREBBP (16p13.3)

REVIEW articles automatic search in PubMed

Last year articles automatic search in PubMed

All articles automatic search in PubMed

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For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.

ICD-Topo	C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho	9837/3 T lymphoblastic leukaemia/lymphoma
ICD-Morpho	9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS
Atlas_Id	1018


	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.

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 / cell stem 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.
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.


	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.

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.



	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.

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	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	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	CREBBP is composed of 31 exons.
Protein	The protein encoded shows intrinsic histone acetyltransferase activity and shares regions of very high sequence similarity with protein p300.

	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.



	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.

Mitelman database	t(8;16)(p11;p13)
arrayMap (UZH-SIB Zurich)	Topo ( C42) Morph ( 9837/3) - [auto + random 100 samples .. if exist ] [tabulated segments]
arrayMap (UZH-SIB Zurich)	Topo ( C42) Morph ( 9861/3) - [auto + random 100 samples .. if exist ] [tabulated segments]

Mitelman database	KAT6A/CREBBP [MCList] KAT6A (8p11.21) CREBBP (16p13.3)
TICdb	KAT6A/CREBBP KAT6A (8p11.21) CREBBP (16p13.3)

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