Atlas of Genetics and Cytogenetics in Oncology and Haematology


Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

t(6;11)(q21;q23) KMT2A/FOXO3

Written2015-01Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho 9811/3 B lymphoblastic leukaemia/lymphoma, NOS
ICD-Morpho 9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS
Atlas_Id 1128

Clinics and Pathology

Disease Acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and other lyphoproliferative diseases.
Epidemiology Eleven cases of t(6;11)(q21;q23) have been described so far: 5 cases of AML (2 M5a-AML, 1 M2-AML, 2 AML not otherwise specified (NOS)), 3 cases of pediatric ALL, 1 case of acute undifferentiated leukemia (AUL), 1 case of prolymphocytic leukemia, and 1 case of peripheral T-cell lymphoma (Heim et al., 1992; Hillion et al., 1997; Bernard et al., 1998; Wong et al., 1999; Stark et al., 2004; Andersen et al., 2005; Helbig et al., 2006; Zuna et al., 2009; Meyer et al., 2013; Parkin et al., 2013). However, the formation of a hybrid KMT2A/FOXO3 was ascertained only in 5 of these 11 cases, namely in the M2-AML, in the AUL, and in the 3 pediatric ALLs (Hillion et al., 1997; Bernard et al., 1998; Zuna et al., 2009; Meyer et al., 2013). The involvement of KMT2A was ascertained in another case (an AML-NOS, Stark et al., 2004), while other cases may have other gene rearrangements instead. Five of the 5 cases with a proved KMT2A/FOXO3 hybrid gene were therapy-related leukemias: the M2-AML occured 2 years after treatment for Hodgkin disease, the AUL also occured after Hodgkin disease, a pro-B ALL occured 2.5 years after treatment for a M3-AML with the classical t(15;17), and the 2 other ALLs were also therapy-induced leukemia cases. Also, another case, a M5a occured after radiotherapy for carcinoma of the larynx. There was 6 male and 5 female patients, Median age was 40-45 years (range: ? (pediatric case) - 80). The 5 patients with proved KMT2A/FOXO3 hybrid gene were: a boy and a girl, a F/15 yrs, M/22 yrs, and a M/40 yrs.
Prognosis Scarce data (34months+ survival in one of the ALLs with proved KMT2A/FOXO3 hybrid gene).

Cytogenetics

Cytogenetics Morphological The t(6;11)(q21;q23) is the sole abnormality in 5 of 9 cases, and in 2 of 3 cases with proved KMT2A/FOXO3 hybrid gene.

Genes involved and Proteins

Gene Name FOXO3
Location 6q21
Protein 673 amino acids. FOXO3 has both a NLS (nuclear localization signal, amino acids 249-251, 269-271) and a NES (nuclear export signal, amino acids 386-396), possess a forkhead domain (DNA-binding domain, amino acids 148-257) and a transactivation domain (amino acids 1251-673). FOXO3 is a transcription factor which recognizes and binds to the DNA consensus sequence [AG]TAAA[TC]A. FOXO transcription factors are key targets of the insulin PI3K-Akt signalling pathway. AKT-induced phosphorylation at Thr32, Ser253 and Ser315 results in the export of FOXO3 from the nucleus to the cytoplasm. SGK1 (6q23.2) also downregulates FOXO3 through phosphorylation at Thr32, Ser253 and Ser315. YWHAB (14-3-3-beta, 20q13.12) and YWHAZ (14-3-3-zeta, 8q22.3) bind FOXO3, decrease FOXO3 binding to DNA, and promote FOXO nuclear export. Lys242, Lys245 and Lys259 of FOXO3 are acetylated by CREBBP (16p13.3) to decrease its DNA affinity IKBKB (8p11.21) induces the phosphorylation of FOXO3 at Ser644 and induces proteasome dependent degradation of FOXO3. SIRT1 (10q21.3), SIRT2 (19q13.2), and SIRT3 (11p15.5) contribute to FOXO3 deacetylation, and promote FOXO3 poly-ubiquitination and degradation. Lysine residues K242, K259, K290 and K569 of FOXO3 are likely the sites for ubiquitination. FOXO transcription factors induce apoptosis, promote cell cycle arrest at the transition G1/S, up-regulate genes involved in DNA repair, allow detoxification of reactive oxygen species; they are also implicated in glucose metabolism and autophagy; FOXO3 induces expression of target genes involved in stress resistance. FOXO transcription factors may regulate lifespan and increase longevity, and may act as tumour suppressors (Tsai et al., 2007; Dobson et al., 2011; Wang et al., 2012; Menniti et al., 2014; Tseng et al., 2014; reviews in Greer and Brunet, 2008; Calnan and Brunet, 2008; Webb and Brunet, 2014).
Gene Name KMT2A
Location 11q23.3
Note KMT2A (HGNC official name!) is better known as MLL.
Protein 3969 amino acids; Transcriptional regulatory factor. MLL is known to be associated with more than 30 proteins, including the core components of the SWI/SNF chromatin remodeling complex and the transcription complex TFIID. MLL binds promotors of HOX genes through acetylation and methylation of histones. MLL is a major regulator of hematopoesis and embryonic development, through regulation of HOX genes expression regulation (HOXA9 in particular).

Result of the chromosomal anomaly

Hybrid gene
Note A MLL split was detected in one case (Stark et al., 2004), and a hybrid MLL/FOXO3 in 5 additional cases (Hillion et al., 1997; Bernard et al., 1998; Zuna et al., 2009; Meyer et al., 2013).
Description In-frame fusion of MLL exon 1 to 7, 8, or 11 to the second exon of FOXO3.
  
Fusion Protein
 
  MLL/FOXO3 Fusion Protein
Description MLL N-term fused to FOXO3 from amino acid 208 to 673.
  

To be noted

Additional cases are needed to delineate the epidemiology of this rare entity:
you are welcome to submit a paper to our new Case Report section.

Bibliography

Centromeric breakage and highly rearranged chromosome derivatives associated with mutations of TP53 are common in therapy-related MDS and AML after therapy with alkylating agents: an M-FISH study.
Andersen MK, Christiansen DH, Pedersen-Bjergaard J.
Genes Chromosomes Cancer. 2005 Apr;42(4):358-71.
PMID 15645489
 
A new case of translocation t(6;11)(q21;q23) in a therapy-related acute myeloid leukemia resulting in an MLL-AF6q21 fusion.
Bernard OA, Hillion J, Le Coniat M, Berger R.
Genes Chromosomes Cancer. 1998 Jul;22(3):221-4.
PMID 9624533
 
The FoxO code.
Calnan DR, Brunet A.
Oncogene. 2008 Apr 7;27(16):2276-88. doi: 10.1038/onc.2008.21. Review.
PMID 18391970
 
Bimodal regulation of FoxO3 by AKT and 14-3-3.
Dobson M, Ramakrishnan G, Ma S, Kaplun L, Balan V, Fridman R, Tzivion G.
Biochim Biophys Acta. 2011 Aug;1813(8):1453-64. doi: 10.1016/j.bbamcr.2011.05.001. Epub 2011 May 19.
PMID 21621563
 
FOXO transcription factors in ageing and cancer.
Greer EL, Brunet A.
Acta Physiol (Oxf). 2008 Jan;192(1):19-28. doi: 10.1111/j.1748-1716.2007.01780.x. Review.
PMID 18171426).
 
Re-emergence in remission of primary clone in acute myelogenous leukaemias with multiple chromosomal aberrations at diagnosis.
Heim S, Sørensen AG, Christensen BE, Pedersen NT.
Br J Haematol. 1992 Oct;82(2):332-6.
PMID 1419815
 
The achievement of complete molecular remission after autologous stem cell transplantation for T-cell lymphoma with associated hypereosinophilia, rare aberration t(6;11) and elevated IL-4 and IgE.
Helbig G, Stella-Holowiecka B, Bober G, Majewski M, Grzegorczyk J, Wozniczka K, Kruzel T, Dziaczkowska J, Najda J, Wojnar J, Holowiecki J.
Haematologica. 2006 Aug;91(8 Suppl):ECR42. No abstract available.
PMID 16923526
 
AF6q21, a novel partner of the MLL gene in t(6;11)(q21;q23), defines a forkhead transcriptional factor subfamily.
Hillion J, Le Coniat M, Jonveaux P, Berger R, Bernard OA.
Blood. 1997 Nov 1;90(9):3714-9.
PMID 9345057
 
SGK1 (serum/glucocorticoid regulated kinase 1)
Menniti M, Iuliano R, D'Antona L, Talarico C, Amato R, Perrotti N
Atlas Genet Cytogenet Oncol Haematol. September 2014
 
The MLL recombinome of acute leukemias in 2013.
Meyer C, Hofmann J, Burmeister T, Gröger D, Park TS, Emerenciano M, Pombo de Oliveira M, Renneville A, Villarese P, Macintyre E, Cavé H, Clappier E, Mass-Malo K, Zuna J, Trka J, De Braekeleer E, De Braekeleer M, Oh SH, Tsaur G, Fechina L, van der Velden VH, van Dongen JJ, Delabesse E, Binato R, Silva ML, Kustanovich A, Aleinikova O, Harris MH, Lund-Aho T, Juvonen V, Heidenreich O, Vormoor J, Choi WW, Jarosova M, Kolenova A, Bueno C, Menendez P, Wehner S, Eckert C, Talmant P, Tondeur S, Lippert E, Launay E, Henry C, Ballerini P, Lapillone H, Callanan MB, Cayuela JM, Herbaux C, Cazzaniga G, Kakadiya PM, Bohlander S, Ahlmann M, Choi JR, Gameiro P, Lee DS, Krauter J, Cornillet-Lefebvre P, Te Kronnie G, Schfer BW, Kubetzko S, Alonso CN, zur Stadt U, Sutton R, Venn NC, Izraeli S, Trakhtenbrot L, Madsen HO, Archer P, Hancock J, Cerveira N, Teixeira MR, Lo Nigro L, Möricke A, Stanulla M, Schrappe M, Sedék L, Szczepan'ski T, Zwaan CM, Coenen EA, van den Heuvel-Eibrink MM, Strehl S, Dworzak M, Panzer-Grümayer R, Dingermann T, Klingebiel T, Marschalek R.
Leukemia. 2013 Nov;27(11):2165-76. doi: 10.1038/leu.2013.135. Epub 2013 Apr 30.
PMID 23628958
 
Clonal evolution and devolution after chemotherapy in adult acute myelogenous leukemia.
Parkin B, Ouillette P, Li Y, Keller J, Lam C, Roulston D, Li C, Shedden K, Malek SN.
Blood. 2013 Jan 10;121(2):369-77. doi: 10.1182/blood-2012-04-427039. Epub 2012 Nov 21.
PMID 23175688
 
Classical and molecular cytogenetic abnormalities and outcome of childhood acute myeloid leukaemia: report from a referral centre in Israel.
Stark B, Jeison M, Gabay LG, Mardoukh J, Luria D, Bar-Am I, Avrahami G, Kapeliushnik Y, Sthoeger D, Herzel G, Steinberg DM, Cohen IJ, Goshen Y, Stein J, Zaizov R, Yaniv I.
Br J Haematol. 2004 Aug;126(3):320-37.
PMID 15257704
 
Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects of post-translational modification.
Tsai KL, Sun YJ, Huang CY, Yang JY, Hung MC, Hsiao CD.
Nucleic Acids Res. 2007;35(20):6984-94. Epub 2007 Oct 16.
PMID 17940099
 
SIRT3 interactions with FOXO3 acetylation, phosphorylation and ubiquitinylation mediate endothelial cell responses to hypoxia.
Tseng AH, Wu LH, Shieh SS, Wang DL.
Biochem J. 2014 Nov 15;464(1):157-68. doi: 10.1042/BJ20140213.
PMID 25162939
 
Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation.
Wang F, Chan CH, Chen K, Guan X, Lin HK, Tong Q.
Oncogene. 2012 Mar 22;31(12):1546-57. doi: 10.1038/onc.2011.347. Epub 2011 Aug 15.
PMID 21841822
 
FOXO transcription factors: key regulators of cellular quality control.
Webb AE, Brunet A.
Trends Biochem Sci. 2014 Apr;39(4):159-69. doi: 10.1016/j.tibs.2014.02.003. Epub 2014 Mar 13. Review.
PMID 24630600
 
T-cell prolymphocytic leukemia with a novel translocation (6;11)(q21;q23).
Wong KF, Chan JK, Sin VC.
Cancer Genet Cytogenet. 1999 Jun;111(2):149-51.
PMID 10347553
 
Covert preleukemia driven by MLL gene fusion.
Zuna J, Burjanivova T, Mejstrikova E, Zemanova Z, Muzikova K, Meyer C, Horsley SW, Kearney L, Colman S, Ptoszkova H, Marschalek R, Hrusak O, Stary J, Greaves M, Trka J.
Genes Chromosomes Cancer. 2009 Jan;48(1):98-107. doi: 10.1002/gcc.20622.
PMID 18932267
 

Citation

This paper should be referenced as such :
Huret JL
t(6;11)(q21;q23) KMT2A/FOXO3;
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Anomalies/t0611q21q23ID1128.html


Other genes implicated (Data extracted from papers in the Atlas) [ 3 ]

Genes FOXO3 FOXO4 KMT2A

Translocations implicated (Data extracted from papers in the Atlas)

 t(6;11)(q21;q23) KMT2A/FOXO3

External links

KMT2A (11q23.3) FOXO3 (6q21)

KMT2A (11q23.3) FOXO3 (6q21)

Mitelman databaset(6;11)(q21;q23) [Case List]    t(6;11)(q21;q23) [Association List] Mitelman database (CGAP - NCBI)
arrayMapTopo ( C42) Morph ( 9811/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapTopo ( C42) Morph ( 9861/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
 
COSMIC_fusionKMT2A/FOXO3 KMT2A (11q23.3) FOXO3 (6q21)   [fusion1795]   [fusion1796]   [fusion1813]   [fusion1814]  
TICdbKMT2A/FOXO3  KMT2A (11q23.3) FOXO3 (6q21)
 
Disease databaset(6;11)(q21;q23) KMT2A/FOXO3
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Tue Mar 14 13:54:56 CET 2017


Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.