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

2015-01-01   Jean-Loup Huret 

1.Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

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).

Genes Involved and Proteins

Gene name
FOXO3 (forkhead box O3A)
Location
6q21
Protein description
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).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).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 (myeloid/lymphoid or mixed lineage leukemia)
Location
11q23.3
Note
KMT2A (HGNC official name!) is better known as MLL.

Result of the Chromosomal Anomaly

Description

In-frame fusion of MLL exon 1 to 7, 8, or 11 to the second exon of FOXO3.
Atlas Image
MLL/FOXO3 Fusion Protein

Description

MLL N-term fused to FOXO3 from amino acid 208 to 673.

Bibliography

Pubmed IDLast YearTitleAuthors
156454892005Centromeric 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 et al
96245331998A new case of translocation t(6;11)(q21;q23) in a therapy-related acute myeloid leukemia resulting in an MLL-AF6q21 fusion.Bernard OA et al
183919702008The FoxO code.Calnan DR et al
216215632011Bimodal regulation of FoxO3 by AKT and 14-3-3.Dobson M et al
181714262008FOXO transcription factors in ageing and cancer.Greer EL et al
14198151992Re-emergence in remission of primary clone in acute myelogenous leukaemias with multiple chromosomal aberrations at diagnosis.Heim S et al
169235262006The 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 et al
93450571997AF6q21, a novel partner of the MLL gene in t(6;11)(q21;q23), defines a forkhead transcriptional factor subfamily.Hillion J et al
236289582013The MLL recombinome of acute leukemias in 2013.Meyer C et al
231756882013Clonal evolution and devolution after chemotherapy in adult acute myelogenous leukemia.Parkin B et al
152577042004Classical and molecular cytogenetic abnormalities and outcome of childhood acute myeloid leukaemia: report from a referral centre in Israel.Stark B et al
179400992007Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects of post-translational modification.Tsai KL et al
251629392014SIRT3 interactions with FOXO3 acetylation, phosphorylation and ubiquitinylation mediate endothelial cell responses to hypoxia.Tseng AH et al
218418222012Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation.Wang F et al
246306002014FOXO transcription factors: key regulators of cellular quality control.Webb AE et al
103475531999T-cell prolymphocytic leukemia with a novel translocation (6;11)(q21;q23).Wong KF et al
189322672009Covert preleukemia driven by MLL gene fusion.Zuna J et al

Summary

Fusion gene

KMT2A/FOXO3 KMT2A (11q23.3) FOXO3 (6q21) COF 1795 1796 1813 1814|KMT2A/FOXO3 KMT2A (11q23.3) FOXO3 (6q21) TIC

Citation

Jean-Loup Huret

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

Atlas Genet Cytogenet Oncol Haematol. 2015-01-01

Online version: http://atlasgeneticsoncology.org/haematological/1128/t(6;11)(q21;q23)

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