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|Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France|
|Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France|
|Abstract||Review on the t(6;11)(q27;q23) involving KMT2A (better known as MLL), and AFDN (Afadin), also known as AF6 or MLLT4. It occurs in acute myeloid leukemia, at times treatment-related leukemia, B lymphoblastic leukemia, and T-cell lymphoblastic leukemia. It carries a poor prognosis.|
|Keywords||Chromosome 6; chromosome 11; t(6;11)(q27;q23); KMT2A; MLL; AFDN; Afadin; AF6; MLLT4; acute myeloid leukemia; treatment-related leukemia; B lymphoblastic leukemia; T-cell lymphoblastic leukemia.|
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|ICD-Morpho||9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS|
|ICD-Morpho||9920/3 Therapy-related myeloid neoplasms|
|ICD-Morpho||9807/3 Mixed phenotype acute leukaemia with t(v;11q23); MLL rearranged|
|ICD-Morpho||9813/3 B lymphoblastic leukaemia/lymphoma with t(v;11q23); MLL rearranged|
|ICD-Morpho||9837/3 T lymphoblastic leukaemia/lymphoma|
|Note|| Herein below, the well-known term "MLL" will be used, instead of the poorly known term "KMT2A"
A total of 135 different MLL rearrangements have been identified so far (Meyer et al., 2017).
|Other names||t(6;11)(q27;q23) MLL/MLLT4|
|t(6;11)(q27;q23) G- banding - Courtesy Diane H. Norback, Eric B. Johnson, Sara Morrison-Delap Cytogenetics at theWaisman Center (left and middle), and Jean-Luc Lai (right).|
2. Clinics and Pathology
|Note|| The incidence of 11q23 abnormalities in infants with acute lymphoblastic leukemia (ALL) ranges from 60% to 80%., and from 4.5% to 5.7% among children who are older than 1 year and have ALL. The t(4;11)(q21;q23) MLL / AFF1, one of the most common 11q23 abnormalities, occurs in 2% of children and adults with ALL (Raimondi 2004). |
The incidence of 11q23 abnormalities in children with acute myeloid leukemia (AML) ranges from 15% to 25%. In children younger than 2 years, the peak incidence of 11q23/MLL gene rearrangements is 50%-60%.
The incidence of 11q23 abnormalities in adults with AML is approximately 5% (Coenen et al., 2012).
The incidence of 11q23 abnormalities among adult ALL cases is about 10% (Pui et al., 2004).
|Disease|| Translocation t(6;11) represent about 5% of acute leukemia with 11q23/MLL rearrangement and is more frequent in AML than in ALL. Different studies are available, each involving specific groups of patients, and they cannot be pooled in one meta-analysis: |
In a large study on 2,345 acute leukemia patients with 11q23/MLL rearrangement, there were 1,420 patients diagnosed with ALL (61%), 872 diagnosed with AML (37%) and 7 with MDS; 38 were mixed lineage leukemia (1.6%), 4 lymphomas, and 4 other. Of these 2,345 patients with MLL rearrangements, there was 95 cases of t(6;11). They represented 4% of the cases. Of these 95 cases, there were 26 ALL, 68 AML, and 1 "other"; two of them were 2 treatment related leukemia. Translocation t(6;11) was found in 7.8% of AML with MLL rearrangements and 1.8% of ALL with MLL rearrangements. There were 59 cases of T-cell ALL in this series of 2,345 acute leukemia patients. T-ALL was mainly composed of AFDN (AF6, MLLT4) and MLLT1 (ENL) gene fusions: there were 23 AFDN (AF6, MLLT4) cases and 22 MLLT1 (ENL) cases (Meyer et al., 2017).
In a series of 550 cases with an 11q23 rearrangement, 30 cases (5.5%) were shown to have a t(6;11)(q27;q23) There were 27 AMLs (26 de novo and 1 secondary, 3 M1, 2 M2, 8 M4, 1 M4/5, 13 M5) and 3 infant/childhood ALL, 1 being a T-ALL (Martineau et al., 1998).
In a study of 756 childhood AML with 11q23 rearrangement, 35 (5%) showed a t(6;11). The disease was an AML-M1 in 15%, AML-M2 in 6%, AML-M4 in 35%, AML-M5 in 41% (Balgobind et al., 2009).
In a study of 415 adult AML cases (389 de novo and 26 treatment-related AML), 54 were rearranged for MLL (31 MLL-fusions and 23 MLL partial tandem duplications (PTD)), 8 of which (26% of 11q23 rearrangements, 1,9% of adult AML cases) were t(6;11) cases. There was 2 AML-M1, 1 AML-M2, 2 AML-M4, 3 AML-M5 (Lavallee et al 2015). 11q23 rearrangements were identified in 118 adult AML cases (85 de novo and 33 t-AML). A t(6;11) (n=17) was found in 14% of 11q23 rearrangements (Grossmann). Out of 2667 adults with de novo AML, 16 patients (0.6%) were identified with t(6;11). there was 3 M1, 7 M4, 5 M5 (Blum et al., 2004).
|Epidemiology|| In the large study of 2,345 acute leukemia patients with 11q23-MLL-rearrangement, there was 876 infants, 671 "pediatric" cases (infants excluded), and 798 adults. Of the the 95 cases with t(6;11) in this study, median age was 19 years, with 3 infant, 44 pediatric, and 48 adult cases; this abnormality is rare in infants (0,3%) and more frequent in children and adults: 6,6 and 6% respectively. Sex ratio was 45M/50F. Mean age of T-cell ALL cases with t(6;11) was 17 years, with 14 pediatric and 9 adult cases. Sex ratio was 11M/12F (Meyer et al., 2017). In another study of t(6;11)(q27;q23) acute leukemia, median age was 30-35 years (range 0.5-72, with 2 infant cases and 6 other children under 16). Sex ratio was 17M/13F (57%) (Martineau et al., 1998). |
In a study of 35 childhood AMLs, median age 12 years (8% were infant cases, 34% were aged 2-9 yrs, and 57% were older children). M/F was 19/16 (54%) (Balgobind et al., 2009).
On 8 adult AML cases : age were 22-58 years, and sex ratio was 3M/5F (Lavallee et al 2015). Median age of adults with de novo AML was 45 years (range 22-65) in another study and sex ratio was 7M/8F (Blum et al., 2004).
|Clinics||Central nervous system involvement was found in 15% of 35 cases of childhood 11q23/MLL-rearranged acute myeloid leukemia (Balgobind et al., 2009)|
|Prognosis||Complete remission (CR) was obtained in 23 of 26 AML cases, but median survival was only 12 months (Martineau et al., 1998). The 35 patients with a t(6;11)(q27;q23) had the worst outcome compared to other childhood 11q23/MLL-rearranged acute myeloid leukemia groups: 5-year event free survival (EFS) was 11% (± 5%) and 5-year overall survival (OS) was 22% (Balgobind et al., 2009). CR was achieved in 69% of adults with de novo AML (11 of 16 patients), but CR duration was short (median 9 months). The estimated probability of 2-year survival was 13%. Both long-term survivors received allogeneic stem cell transplantation. The estimated probability of 2-year survival of patients reported in the literature was 15% (Blum et al., 2004). However, as there are many progresses in therapy, one cannot rely on survival studies made 10 or 20 years ago.|
|Cytogenetics Morphological||In a series of 30 cases with t(6;11)(q27;q23), (27 AMLs and 3 ALLs). The t(6;11) was the sole abnormality in 24 cases (at least in a subclone), +der(6)t(6;11), +8, +19 and +21 were found in 10% (3 times) each. All three patients with AML-M1 had additional abnormalities. (Martineau et al., 1998). In a series of adults with de novo AML, the t(6;11) was the sole abnormality in 12/15 cases; der(6)t(6;11) and +8 were found in one case each (Blum et al., 2004)|
|Cytogenetics Molecular||The t(6;11) translocation can escape recognition: chromosome 6 involvement may be overlooked and the abnormality may be missinterpreted as a del(11q), with conventional banding techniques; FISH techniques necessary.|
4. Genes involved and Proteins
|Note||Frequent KRAS and NRAS mutations were found (30% and 18% respectively) in AML adult cases and there was MECOM overexpression in 100% (Grossmann et al., 2013).There was high expression levels of NKX2-3 and MECOM in AML adult cases. (Lavallee et al 2015). Methylation of lysine79 of histone H3 (H3K79) is a prerequisite for maintenance of RNA transcription. MLL/AFF1 (AF4), MLL/ MLLT3 (AF9), MLL/MLLT1 (ENL), MLL/MLLT10 (AF10) and MLL/AFDN (AF6, MLLT4), result in an increased and extended H3K79 methylation (Meyer et al., 2017).|
|Note||Better known as MLL|
|Dna / Rna||37 exons, spanning about 120 kb; 13-15 mRNA|
|Protein||3969 amino acids, 431 kDa; 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).|
|Note||AFDN was previously called MLLT4 (myeloid/lymphoid or mixed-lineage leukemia; translocated to, 4) or AF6 (ALL1 fused gene from chromosome 6)|
|Protein|| The protein, called afadin, is a scaffolding protein with a role in cell-cell junctional complexes (adherens junctions and in tight junctions). The transmembrane proteins cadherins and nectins interact with other proteins through their cytoplasmic domain to form adherens junctions. CTNNA1, CTNNA2 or CTNNA3 (α-catenins) /CTNNB1 (β-catenin) links cadherins to the actin cytoskeleton and afadin links nectins to the actin cytoskeleton (Boettner et al., 2000; Tachibana et al., 2000; Bégay-Müller et al., 2002). Afadin plays an essential role in regulating apical-basal polarity and adherens junction integrity (Rakotomamonjy et al., 2017). |
Loss of expression or lower expression of afadin is found in pancreatic cancer, and is correlated with poor prognosis in colon cancer and breast cancer, induces cell migration and cell invasion of myometrium in endometrial cancer, where it is associated with high histological grades (Fournier et al., 2011; Sun et al., 2014; Xu et al., 2015; Yamamoto et al., 2015a).
5. Result of the chromosomal anomaly
|Description|| The breakpoint in AFDN (AF6, MLLT4) was determined from two AML, one T-ALL, and one cell line. It was found between exons 1 and 2, corresponding to the junction of amino acid 35 and 36 (Tanabe et al., 1996); i.e. |
In 8 of 8 AML adult cases, MLL exon/intron 8 was fused to AFDN (AF6, MLLT4) exon/intron 1 (Lavallee et al 2015).
In the large study of 95 cases of acute leukemia with t(6;11); the breakpoint in MLL was more often in intron 9 (65% on cases) than it was in other fusions (e.g. AFF1 (AF4): 33%, MLLT3 (AF9): 38%, MLLT1 (ENL): 23%, where intron 11 is equally or more frequent). The breakpoint was in: intron 9: 62 cases, exon 10: 4 cases, intron 10: 15 cases, exon 11: 4 cases, intron 11: 3 cases, exon 12: 2 cases. Only in MLL/AFDN cases were observed very unusual MLL breakpoints (n=4), within intron 21 and 23. The authors pointed out that "This is quite important because such a far away downstream breakpoint includes the complete PHD1-3, the BD domain as well as the complete ePHD4 domain of MLL into the fusion protein with AFDN (AF6, MLLT4). These additional 581 amino acids could be an important hint for the importance of these MLL domains in T-ALL. The PHD1-3 and bromodomain exert important regulatory functions to the MLL N-terminus, like chromatin reading, protein stability or PPIE (CYP33) binding. In the latter case, binding of the BMI1 repressor complex will reverse the function of the MLL/AFDN fusion by repressing gene transcription" (Meyer et al., 2017).
|Oncogenesis||While AFDN localizes in the cytoplasm, MLL/AFDN localizes in the nucleus, leading to aberrant activation of RAS and of its downstream targets (Deshpande et al., 2013; Manara et al. 2014).|
|The LIM domain protein Lmo2 binds to AF6, a translocation partner of the MLL oncogene|
|Bégay-Müller V, Ansieau S, Leutz A|
|FEBS Lett 2002 Jun 19;521(1-3):36-8|
|Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study|
|Balgobind BV, Raimondi SC, Harbott J, Zimmermann M, Alonzo TA, Auvrignon A, Beverloo HB, Chang M, Creutzig U, Dworzak MN, Forestier E, Gibson B, Hasle H, Harrison CJ, Heerema NA, Kaspers GJ, Leszl A, Litvinko N, Nigro LL, Morimoto A, Perot C, Pieters R, Reinhardt D, Rubnitz JE, Smith FO, Stary J, Stasevich I, Strehl S, Taga T, Tomizawa D, Webb D, Zemanova Z, Zwaan CM, van den Heuvel-Eibrink MM|
|Blood 2009 Sep 17;114(12):2489-96|
|Adult de novo acute myeloid leukemia with t(6;11)(q27;q23): results from Cancer and Leukemia Group B Study 8461 and review of the literature|
|Blum W, Mrózek K, Ruppert AS, Carroll AJ, Rao KW, Pettenati MJ, Anastasi J, Larson RA, Bloomfield CD|
|Cancer 2004 Sep 15;101(6):1420-7|
|The junctional multidomain protein AF-6 is a binding partner of the Rap1A GTPase and associates with the actin cytoskeletal regulator profilin|
|Boettner B, Govek EE, Cross J, Van Aelst L|
|Proc Natl Acad Sci U S A 2000 Aug 1;97(16):9064-9|
|11q23 rearrangements in de novo childhood acute myeloid leukemia|
|Coenen EA, Harbott J, Zwaan CM, Raimondi SC, van den Heuvel-Eibrink MM|
|Atlas Genet Cytogenet Oncol Haematol. 2012;16(8):574-581.|
|Leukemic transformation by the MLL-AF6 fusion oncogene requires the H3K79 methyltransferase Dot1l|
|Deshpande AJ, Chen L, Fazio M, Sinha AU, Bernt KM, Banka D, Dias S, Chang J, Olhava EJ, Daigle SR, Richon VM, Pollock RM, Armstrong SA|
|Blood 2013 Mar 28;121(13):2533-41|
|Loss of AF6/afadin, a marker of poor outcome in breast cancer, induces cell migration, invasiveness and tumor growth|
|Fournier G, Cabaud O, Josselin E, Chaix A, Adélaïde J, Isnardon D, Restouin A, Castellano R, Dubreuil P, Chaffanet M, Birnbaum D, Lopez M|
|Oncogene 2011 Sep 8;30(36):3862-74|
|High incidence of RAS signalling pathway mutations in MLL-rearranged acute myeloid leukemia|
|Grossmann V, Schnittger S, Poetzinger F, Kohlmann A, Stiel A, Eder C, Fasan A, Kern W, Haferlach T, Haferlach C|
|Leukemia 2013 Sep;27(9):1933-6|
|The transcriptomic landscape and directed chemical interrogation of MLL-rearranged acute myeloid leukemias|
|Lavallée VP, Baccelli I, Krosl J, Wilhelm B, Barabé F, Gendron P, Boucher G, Lemieux S, Marinier A, Meloche S, Hébert J, Sauvageau G|
|Nat Genet 2015 Sep;47(9):1030-7|
|MLL-AF6 fusion oncogene sequesters AF6 into the nucleus to trigger RAS activation in myeloid leukemia|
|Manara E, Baron E, Tregnago C, Aveic S, Bisio V, Bresolin S, Masetti R, Locatelli F, Basso G, Pigazzi M|
|Blood 2014 Jul 10;124(2):263-72|
|The t(6;11)(q27;q23) translocation in acute leukemia: a laboratory and clinical study of 30 cases|
|Martineau M, Berger R, Lillington DM, Moorman AV, Secker-Walker LM|
|EU Concerted Action 11q23 Workshop participants Leukemia|
|The MLL recombinome of acute leukemias in 2017|
|Meyer C, Burmeister T, Gröger D, Tsaur G, Fechina L, Renneville A, Sutton R, Venn NC, Emerenciano M, Pombo-de-Oliveira MS, Barbieri Blunck C, Almeida Lopes B, Zuna J, Trka J, Ballerini P, Lapillonne H, De Braekeleer M, Cazzaniga G, Corral Abascal L, van der Velden VHJ, Delabesse E, Park TS, Oh SH, Silva MLM, Lund-Aho T, Juvonen V, Moore AS, Heidenreich O, Vormoor J, Zerkalenkova E, Olshanskaya Y, Bueno C, Menendez P, Teigler-Schlegel A, Zur Stadt U, Lentes J, Göhring G, Kustanovich A, Aleinikova O, Schäfer BW, Kubetzko S, Madsen HO, Gruhn B, Duarte X, Gameiro P, Lippert E, Bidet A, Cayuela JM, Clappier E, Alonso CN, Zwaan CM, van den Heuvel-Eibrink MM, Izraeli S, Trakhtenbrot L, Archer P, Hancock J, Möricke A, Alten J, Schrappe M, Stanulla M, Strehl S, Attarbaschi A, Dworzak M, Haas OA, Panzer-Grümayer R, Sedék L, Szczepański T, Caye A, Suarez L, Cavé H, Marschalek R|
|Leukemia 2017 Jul 13|
|Acute lymphoblastic leukemia|
|Pui CH, Relling MV, Downing JR|
|N Engl J Med 2004 Apr 8;350(15):1535-48|
|11q23 rearrangements in childhood acute lymphoblastic leukemia|
|Atlas Genet Cytogenet Oncol Haematol. 2004;8(2):97-102.|
|Afadin controls cell polarization and mitotic spindle orientation in developing cortical radial glia|
|Rakotomamonjy J, Brunner M, Jüschke C, Zang K, Huang EJ, Reichardt LF, Chenn A|
|Neural Dev 2017 May 8;12(1):7|
|Disrupted interaction between CFTR and AF-6/afadin aggravates malignant phenotypes of colon cancer|
|Sun TT, Wang Y, Cheng H, Xiao HZ, Xiang JJ, Zhang JT, Yu SB, Martin TA, Ye L, Tsang LL, Jiang WG, Xiaohua J, Chan HC|
|Biochim Biophys Acta 2014 Mar;1843(3):618-28|
|Two cell adhesion molecules, nectin and cadherin, interact through their cytoplasmic domain-associated proteins|
|Tachibana K, Nakanishi H, Mandai K, Ozaki K, Ikeda W, Yamamoto Y, Nagafuchi A, Tsukita S, Takai Y|
|J Cell Biol 2000 Sep 4;150(5):1161-76|
|Analysis of the t(6;11)(q27;q23) in leukemia shows a consistent breakpoint in AF6 in three patients and in the ML-2 cell line|
|Tanabe S, Zeleznik-Le NJ, Kobayashi H, Vignon C, Espinosa R 3rd, LeBeau MM, Thirman MJ, Rowley JD|
|Genes Chromosomes Cancer 1996 Apr;15(4):206-16|
|Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression|
|Xu Y, Chang R, Peng Z, Wang Y, Ji W, Guo J, Song L, Dai C, Wei W, Wu Y, Wan X, Shao C, Zhan L|
|Nat Commun 2015 May 26;6:7184|
|Loss of AF-6/afadin induces cell invasion, suppresses the formation of glandular structures and might be a predictive marker of resistance to chemotherapy in endometrial cancer|
|Yamamoto T, Mori T, Sawada M, Matsushima H, Ito F, Akiyama M, Kitawaki J|
|BMC Cancer 2015 Apr 12;15:275|
|This paper should be referenced as such :|
|Atlas Genet Cytogenet Oncol Haematol. 2018;22(7):308-312.|
|Free journal version : [ pdf ] [ DOI ]|
|On line version : https://atlasgeneticsoncology.usal.es/classic/Anomalies/t0611ID1015.html|
|History of this paper:|
|Huret, JL. t(6;11)(q27;q23). Atlas Genet Cytogenet Oncol Haematol. 1997;1(2):87-88.|
8. Translocations implicated (Data extracted from papers in the Atlas)
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