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

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.
Atlas Image
MLL/FOXO3 Fusion Protein

Description

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

Bibliography

Pubmed IDLast YearTitleAuthors

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)