AFF1 (AF4/FMR2 family, member 1), KMT2A (myeloid/lymphoid or mixed lineage leukemia), "> t(4;11)(q21;q23) KMT2A/AFF1

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t(4;11)(q21;q23) KMT2A/AFF1

Written1997-12Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Updated2017-02Rawan Faramand, Samir Dalia
Moffitt Cancer Center, Tampa, FL (RF); Oncology and Hematology, Mercy Clinic Joplin, MO USA - sdalia@gmail.com (SD)

Abstract , Review on t(4;11)(q21;q23) KMT2A/AFF1 with data on clinics and the genes involved.

Keywords Chromosome 4; Chromosome 11; KMT2A; MLL; AFF1; Acute myeloid leukemia; Therapy-related myeloid leukemia; Acute lymphoblastic leukemia

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho 9807/3 Mixed phenotype acute leukaemia with t(v;11q23); MLL rearranged
ICD-Morpho 9811/3 B lymphoblastic leukaemia/lymphoma, NOS
ICD-Morpho 9813/3 B lymphoblastic leukaemia/lymphoma with t(v;11q23); MLL rearranged
ICD-Morpho 9837/3 T lymphoblastic leukaemia/lymphoma
ICD-Morpho 9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS
ICD-Morpho 9920/3 Therapy-related myeloid neoplasms
Atlas_Id 1051
 
  t(4;11)(q21;q23) ) G-banding (left) - Courtesy Diane H. Norback, Eric B. Johnson, and Sara Morrison-Delap, http://www.slh.wisc.edu/cytogenetics>; R- banding (right) - Jean Loup Huret (top), - Courtesy Christiane Charrin (middle), - Courtesy Hossein Mossafa (bottom and FISH).

Clinics and Pathology

Disease Translocation t(4;11)(q21;q23) leads to the production of the MLL/AF4 (now called KMT2A and AFF1 respectively) fusion gene. It accounts for approximately 5-10% of newly diagnosed cases of Acute Lymphoblastic Leukemia (ALL) mainly in children. Rarely this translocation has been reported in biphenotypic ALL, T-ALL, and in acute myeloid leukemia usually M4 or M5 subtypes.
Phenotype / cell stem origin The mixed lineage leukemia (MLL) gene located at 11q23 is a frequently seen target of chromosomal translocations in acute leukemias. There are currently over 100 different KMT2A (MLL) rearrangements identified which can occur in both acute myeloid and acute lymphoblastic leukemias, with AFF1 (AF4) being the most frequently recognized fusion gene. Leukemias expressing KMT2A/AFF1, otherwise known as t(4;11)(q21;q23) are mainly diagnosed in patients with pro-B ALL ( Marchesi et al, 2005). Cases of T-ALL, biphoenotypic ALL and AML (M4 and M5 types) has also rarely been reported with one study showing that in 183 total cases with the t(4;11)(q21;q23) only six were AML, one was a T-ALL, and one was a biphenotypic ALL (Johansson Et al, 1998 Leukemia). Treatment related ALL and AML has also been reported in the literature with this translocation.
Epidemiology The majority of cases of t(4;11)(q21;q23) positive ALL occur in infants less than 6 months old, accounting for 50% of ALL in that each group. Translocation (4;11)(q21;q23) is detected in approximately 10% adults with newly diagnosed B-cell ALL, and 30-40% or pro-B ALL subtypes. (Moorman et al. Blood 2007). It can present in older ages with one study showing eleven percent occurring in patients 50 or older. Rarely this translocation can be seen in M4 or M5 AML, T-ALL or treatment related acute leukemia. In treatment related acute leukemia, ALL is more common than AML (Johansson et al, 1998, Leukemia). The disease seems to be more common in females than in males particularly in those who get the disease under six months of age and over 40 years of age.
Clinics Patients typically present with features consistent with more aggressive leukemias, including hyperleukocytosis (median around 200 X 109/l), hepatosplenomegaly and CNS involvement. While DIC is uncommon in most forms of ALL, patients with this subtype of ALL have a higher incidence of DIC at the time of diagnosis. (Pui et al, 1991).
Pathology Blast cells usually display features of early B cell leukemia including heavy chain immunglobulin gene rearrangement, TDT, HLD-DR, CD34, Cd19, CD9 and CD 24 positivity. Expression of CD 10 and T cell antigens is rare. In cases of AML CD 15 and CD65 are positive and nonspecific esterase and myeloperoxidase staining (Carulli et al. 2012).
Treatment Patients with this subtype of ALL have higher risk features at diagnosis and overall poor prognosis. Common treatment for ALL includes an induction, consolidation and maintenance treatment which typically lasts about two years. Drug combinations differ based on region and treating physician but typically including vincristine, a corticosteroid, anthracycline along with L-asparaginase. Cyclophosphamide and etoposide are also part of some treatment plans along with methotrexate or cytarabine. Intrathecal chemotherapy is given during inductoin to prevent CNS involvement. Allogenic bone marrow transplantation is indicated in certain cases as well. In patients with B-cell ALL rituximab is also used to target CD20. It is important to evaluate for minimal residual disease (MRD) by Polymerase chain reaction (PCR) as small studies have shown that MRD positivity after consolidation is associated with higher incidence of relapse and inferior overall survival. However, more data from larger studies is needed to establish evidence based guidelines for treatment of this subset of ALL. (Vey et al, 2012).
In rare cases of t(4;11) AML, induction chemotherapy with antracycline based treatment is indicated followed by consolidation and allogenic bone marrow transplantation.
Prognosis Rearrangement of the MLL gene confers a poor prognosis in both children and adults. Patients with t(4;11)(q21;q23) are categorized as having high risk disease. Remission rates of 75 percent have been seen but median event free survival has been noted of seven months in adults. In children the complete remission rate is around 88% but a median survival of 10 months (Meyer et al, 2006). In one study of infant ALL patients with t(4;11), the five year survival rate was only 29 percent (Hilden et al 2006).

Cytogenetics

 
  i(7q) R- banding - Jean-Loup Huret (left), - Courtesy Christiane Charrin (right).
Additional anomalies Additional abnormalities are found in 1/4 of cases at diagnosis, clonal evolution to hyperploidy is frequent; additional anomalies by decreasing order: i(7q) in 10%, +X, + Mar, +6, +8, +19 , +21, +13, +10, +14; no difference in outcome was found.
Variants Three way complex t(4;11;Var) exist and showed that the crucial event lies on the der(11).

Genes involved and Proteins

Note The primary mode of action in which chromosomal aberrations can occur to the KMT2A (MLL) gene is the reciprocal translocation which results in in-frame fusion transcripts with various partner genes. There are more than 60 recognized translocation partner genes with the most common one being AFF1 (AF4). The translocation leads to the loss of the methyltransferase domain of KMT2A in the KMT2A fusion protein. While there are several hypothesis regarding the mechanism by which the translocation t(4;11)(q21;q23) leads to leukemogenesis, the exact mechanism is not known (Schnittger et al. 2000).
However, KMT2A/AFF1 binds at specific subsets of regulatory elements and direct part of the RUNX1 gene program, and many others; KMT2A/AFF1 binds to the BCL2 gene and directly activates it through DOT1L recruitment, KMT2A/AFF1 also controls the active transcription of MCL1 and represses BCL2L11 (BIM) (Konopleva et al. 2017; Stunnenberg and Martens, 2017.
Gene NameAFF1 (AF4/FMR2 family, member 1)
Location 4q21.3
Note AFF1 is the AF4/FMR2 family member 1, also known as AF4.
Dna / Rna 20 exons, transcript length: 9,390 bps
Protein 1,210 amino acids, 131 kDa; AFF1 is bound to CDK9 and CCNT1 and is present in all major positive transcription elongation factor b (P-TEFb) complexes, which stimulates RNA polymerase elongation (Lu et al., 2014).
Gene NameKMT2A (myeloid/lymphoid or mixed lineage leukemia)
Location 11q23.3
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. KMT2A 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. KMT2A binds promotors of HOX genes through acetylation and methylation of histones. KMT2A 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
Description 5' KMT2A - 3' AFF1; breakpoints are variable.
  
Fusion Protein
Description e.g. 2319 amino acids; 240 kDa; N-term AT hook and DNA methyltransferase from KMT2A fused to AFF1 C-term; the reciprocal ( AFF1/ KMT2A) may or may not be expressed; quite similar to the KMT2A/ MLLT1 fusion protein found with t(11;19)(q23;p13.3)
Expression Localisation Nuclear localization.
  

Bibliography

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The MLL recombinome of acute leukemias
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Acute leukemia with chromosome translocation (4;11): 7 new patients and analysis of 71 cases
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Citation

This paper should be referenced as such :
Faramand R, Dalia S
t(4;11)(q21;q23) KMT2A/AFF1;
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Anomalies/t0411ID1051.html
History of this paper:
Huret, JL. t(9;11)(p22;q23). Atlas Genet Cytogenet Oncol Haematol. 1997;1(2):96-97.
http://documents.irevues.inist.fr/bitstream/handle/2042/32070/12-1997-t0411ID1051.pdf


Other genes implicated (Data extracted from papers in the Atlas) [ 5 ]

Genes AFF1 AFF4 BTK DLX2 KMT2A

Translocations implicated (Data extracted from papers in the Atlas)

 t(4;11)(q21;q23) KMT2A/AFF1

External links

KMT2A (11q23.3) AFF1 (4q21.3)

KMT2A (11q23.3) AFF1 (4q21.3)

Mitelman databaset(4;11)(q21;q23) [Case List]    t(4;11)(q21;q23) [Association List] Mitelman database (CGAP - NCBI)
arrayMapTopo ( C42) Morph ( 9807/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapTopo ( C42) Morph ( 9811/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapTopo ( C42) Morph ( 9813/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapTopo ( C42) Morph ( 9837/3) - 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]
arrayMapTopo ( C42) Morph ( 9920/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
 
COSMIC_fusionKMT2A/AFF1 KMT2A (11q23.3) AFF1 (4q21.3)   [fusion1799]   [fusion1800]   [fusion1801]   [fusion1802]   [fusion1827]   [fusion1828]   [fusion1829]   [fusion1830]   [fusion1947]   [fusion1948]   [fusion1949]   [fusion1951]   [fusion1953]   [fusion1954]   [fusion1955]   [fusion1956]   [fusion1957]   [fusion1958]   [fusion2023]   [fusion2024]   [fusion2066]   [fusion2067]   [fusion2068]   [fusion2073]   [fusion2074]   [fusion2090]   [fusion2091]   [fusion2092]  
TICdbKMT2A/AFF1  KMT2A (11q23.3) AFF1 (4q21.3)
 
Disease databaset(4;11)(q21;q23) KMT2A/AFF1
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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