KMT2A/AFF1 Rawan Faramand, Samir Dalia Moffitt Cancer Center, Tampa, FL (RF); Oncology and Hematology, Mercy Clinic Joplin, MO USA - [email protected] (SD)

KMT2A/AFF1 Rawan Faramand, Samir Dalia Moffitt Cancer Center, Tampa, FL (RF); Oncology and Hematology, Mercy Clinic Joplin, MO USA - Sdalia@Gmail.Com (SD)

Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Leukaemia Section Short Communication t(4;11)(q21;q23) KMT2A/AFF1 Rawan Faramand, Samir Dalia Moffitt Cancer Center, Tampa, FL (RF); Oncology and Hematology, Mercy Clinic Joplin, MO USA - [email protected] (SD)

Published in Atlas Database: February 2017 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0411ID1051.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68755/02-2017-t0411ID1051.pdf DOI: 10.4267/2042/68755

This article is an update of : Huret JL. t(4;11)(q21;q23). Atlas Genet Cytogenet Oncol Haematol 1997;1(2)

Chromosome 4; Chromosome 11; KMT2A; MLL; Abstract AFF1; Acute myeloid leukemia; Therapy-related Review on t(4;11)(q21;q23) KMT2A/AFF1 with myeloid leukemia; Acute lymphoblastic leukemia data on clinics and the genes involved. KEYWORDS Identity

t(4;11)(q21;q23) KMT2A/AFF1 G-banding (left) Top two: - Courtesy Diane H. Norback, Eric B. Johnson, and Sara Morrison-Delap; bottom three: - Courtesy Adriana Zamecnikova; R- banding (right) - Jean Loup Huret (top), - Courtesy Christiane Charrin (middle), - Courtesy Hossein Mossafa (bottom and FISH above). FISH below: Hybridization with Vysis LSI MLL break apart rearrangement probe (Abbott Molecular, US) showing

Atlas Genet Cytogenet Oncol Haematol. 2018; 22(1) 30 t(4;11)(q21;q23) KMT2A/AFF1

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

Atlas Genet Cytogenet Oncol Haematol. 2018; 22(1) 31 t(4;11)(q21;q23) KMT2A/AFF1

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). KMT2A (myeloid/lymphoid or mixed lineage leukemia) Location 11q23.3 Note i(7q) R- banding - Jean-Loup Huret (left), - Better known as MLL Courtesy Christiane Charrin (right). DNA/RNA Additional anomalies 37 exons, spanning about 120 kb; 13-15 mRNA Additional abnormalities are found in 1/4 of cases at Protein diagnosis, clonal evolution to hyperploidy is 3969 amino acids, 431 kDa; Transcriptional frequent; additional anomalies by decreasing order: regulatory factor. KMT2A is known to be associated i(7q) in 10%, +X, + Mar, +6, +8, +19 , +21, +13, with more than 30 proteins, including the core +10, +14; no difference in outcome was found. components of the SWI/SNF chromatin remodeling Variants complex and the transcription complex TFIID. KMT2A binds promotors of HOX genes through Three way complex t(4;11;Var) exist and showed acetylation and methylation of histones. KMT2A is that the crucial event lies on the der(11). a major regulator of hematopoesis and embryonic development, through regulation of HOX genes Genes involved and expression regulation (HOXA9 in particular). proteins Result of the chromosomal Note The primary mode of action in which chromosomal anomaly aberrations can occur to the KMT2A (MLL) gene is the reciprocal translocation which results in in-frame Hybrid gene fusion transcripts with various partner genes. There Description are more than 60 recognized translocation partner 5' KMT2A - 3' AFF1; breakpoints are variable. genes with the most common one being AFF1 Fusion protein (AF4). The translocation leads to the loss of the Description methyltransferase domain of KMT2A in the e.g. 2319 amino acids; 240 kDa; N-term AT hook KMT2A fusion protein. While there are several and DNA methyltransferase from KMT2A fused to hypothesis regarding the mechanism by which the AFF1 C-term; the reciprocal ( AFF1/ KMT2A) may translocation t(4;11)(q21;q23) leads to or may not be expressed; quite similar to the leukemogenesis, the exact mechanism is not known KMT2A/ MLLT1 fusion protein found with (Schnittger et al. 2000). t(11;19)(q23;p13.3)

However, KMT2A/AFF1 binds at specific subsets of Expression / Localisation regulatory elements and direct part of the RUNX1 Nuclear localization. gene program, and many others; KMT2A/AFF1 binds to the BCL2 gene and directly activates it References through DOT1L recruitment, KMT2A/AFF1 also Carulli G, Marini A, Ferreri MI, Azzarà A, Ottaviano V, Lari controls the active transcription of MCL1 and T, Rocco M, Giuntini S, Petrini M. B-cell acute lymphoblastic represses BCL2L11 (BIM) (Konopleva et al. 2017; leukemia with t(4;11)(q21;q23) in a young woman: evolution Stunnenberg and Martens, 2017. into mixed phenotype acute leukemia with additional chromosomal aberrations in the course of therapy. Hematol AFF1 (AF4/FMR2 family, member 1) Rep. 2012 Jul 11;4(3):e15 Location Heerema NA, Arthur DC, Sather H, Albo V, Feusner J, 4q21.3 Lange BJ, Steinherz PG, Zeltzer P, Hammond D, Reaman GH. Cytogenetic features of infants less than 12 months of Note age at diagnosis of acute lymphoblastic leukemia: impact of AFF1 is the AF4/FMR2 family member 1, also the 11q23 breakpoint on outcome: a report of the Childrens known as AF4. Cancer Group. Blood. 1994 Apr 15;83(8):2274-84 DNA/RNA Mancini M, Scappaticci D, Cimino G, Nanni M, Derme V, 20 exons, transcript length: 9,390 bps Elia L, Tafuri A, Vignetti M, Vitale A, Cuneo A, Castoldi G,

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