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

2017-02-01   Rawan Faramand , Rawan Faramand 

1.Moffitt Cancer Center, Tampa, FL (RF); Oncology and Hematology, Mercy Clinic Joplin, MO USA - sdalia@gmail.com (SD)
2.Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France


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

Clinics and Pathology


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 stem cell 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.


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.


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).


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).


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.


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).


Atlas Image
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.


Three way complex t(4;11;Var) exist and showed that the crucial event lies on the der(11).

Genes Involved and Proteins

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).
AFF1 is the AF4/FMR2 family member 1, also known as AF4.
Gene name
AFF1 (AF4/FMR2 family, member 1)
Dna rna description
20 exons, transcript length: 9,390 bps
Protein description
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 name
KMT2A (myeloid/lymphoid or mixed lineage leukemia)
Better known as MLL
Dna rna description
37 exons, spanning about 120 kb; 13-15 mRNA
Protein description
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


5 KMT2A - 3 AFF1; breakpoints are variable
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.

Highly cited references

Pubmed IDYearTitleCitations
306793232019Unraveling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis.36
290165702017Blinatumomab-induced lineage switch of B-ALL with t(4:11)(q21;q23) KMT2A/AFF1 into an aggressive AML: pre- and post-switch phenotypic, cytogenetic and molecular analysis.18
287901052017Impact of cytogenetic abnormalities in adults with Ph-negative B-cell precursor acute lymphoblastic leukemia.17
302035712018KMT2A (MLL) rearrangements observed in pediatric/young adult T-lymphoblastic leukemia/lymphoma: A 10-year review from a single cytogenetic laboratory.12
298067012018Neonatal leukaemia.11
264032242015HMGA2 as a potential molecular target in KMT2A-AFF1-positive infant acute lymphoblastic leukaemia.9
301257572018Retrospective analysis of 36 fusion genes in 2479 Chinese patients of de novo acute lymphoblastic leukemia.8
338958092021Molecular classification improves risk assessment in adult BCR-ABL1-negative B-ALL.7
304784482019Targeting EIF4E signaling with ribavirin in infant acute lymphoblastic leukemia.7
303472682019Clinical Evaluation of Massively Parallel RNA Sequencing for Detecting Recurrent Gene Fusions in Hematologic Malignancies.7
280768412017Clonal evolution in therapy-related neoplasms.7
324148482021Combinatorial efficacy of entospletinib and chemotherapy in patient-derived xenograft models of infant acute lymphoblastic leukemia.5
318859552019Immunotherapy- (Blinatumomab-) Related Lineage Switch of KMT2A/AFF1 Rearranged B-Lymphoblastic Leukemia into Acute Myeloid Leukemia/Myeloid Sarcoma and Subsequently into B/Myeloid Mixed Phenotype Acute Leukemia.5
318071152019Clinical-biological characteristics and treatment outcomes of pediatric pro-B ALL patients enrolled in BCH-2003 and CCLG-2008 protocol: a study of 121 Chinese children.5
286244742017"Exposure to the insecticides permethrin and malathion induces leukemia and lymphoma-associated gene aberrations in vitro".5
286460232017Amlexanox Downregulates S100A6 to Sensitize KMT2A/AFF1-Positive Acute Lymphoblastic Leukemia to TNFα Treatment.5
340887162021A KMT2A-AFF1 gene regulatory network highlights the role of core transcription factors and reveals the regulatory logic of key downstream target genes.4
346571282022Prognostic impact of chromosomal abnormalities and copy number alterations in adult B-cell precursor acute lymphoblastic leukaemia: a UKALL14 study.3
327211242019The RS4;11 cell line as a model for leukaemia with t(4;11)(q21;q23): Revised characterisation of cytogenetic features.3
266488362015Cytogenetic and Molecular Findings in Children with Acute Lymphoblastic Leukemia: Experience of a Single Institution in Argentina.3
335424812021Allogeneic hematopoietic stem cell transplantation for adult patients with t(4;11)(q21;q23) KMT2A/AFF1 B-cell precursor acute lymphoblastic leukemia in first complete remission: impact of pretransplant measurable residual disease (MRD) status. An analysis from the Acute Leukemia Working Party of the EBMT.1
329921022020First report of t(5;11) KMT2A-MAML1 fusion in de novo infant acute lymphoblastic leukemia.1
307014582019Molecular profiling of adult acute myeloid and lymphoid leukemia in a major referral center in Lebanon: a 10-year experience report and review of the literature.1
308722722019Mixed-phenotype acute leukemia with t(4;11)(q21;q23) KMT2A-AFF1-rearranged.1
356859212022Low Prevalence of ETV6::RUNX1 Fusion Gene in a Hispanic Population.0
336463062021Genome-wide interference of ZNF423 with B-lineage transcriptional circuitries in acute lymphoblastic leukemia.0
359333382022Poor treatment responses were related to poor outcomes in pediatric B cell acute lymphoblastic leukemia with KMT2A rearrangements.0
358007672022The immune checkpoint ICOSLG is a relapse-predicting biomarker and therapeutic target in infant t(4;11) acute lymphoblastic leukemia.0
349304532021Daratumumab and venetoclax in combination with chemotherapy provide sustained molecular remission in relapsed/refractory CD19, CD20, and CD22 negative acute B lymphoblastic leukemia with KMT2A-AFF1 transcript.0
345251852021Outcomes of acute lymphoblastic leukemia with KMT2A (MLL) rearrangement: the MD Anderson experience.0
345759042021Genetic and Epigenetic Characterization of a Discordant KMT2A/AFF1-Rearranged Infant Monozygotic Twin Pair.0
340480722021Prognostic impact of KMT2A-AFF1-positivity in 926 BCR-ABL1-negative B-lineage acute lymphoblastic leukemia patients treated in GIMEMA clinical trials since 1996.0
344972212021[Acute leukemia of infants and neonates].0
343490662021[Leukemogenic pathway of infant leukemia with MLL fusion].0
333339662020Outcomes in Pediatric Acute Lymphoblastic Leukemia-A Single-Center Romanian Experience.0
321143712020Osteopontin-c is overexpressed in KMT2A-AFF1 positive pediatric B-cell lymphoblastic leukemia when compared to those with ETV6-RUNX1".0
283322622017Haploidentical peripheral blood stem cell transplantation without irradiation or busulfan after reduced-intensity conditioning for KMT2A(MLL)-rearranged infant B-cell precursor acute lymphoblastic leukemia: Report of two cases.0


No bibliography items were found for this article.


Fusion gene

KMT2A/AFF1 KMT2A (11q23.3) AFF1 (4q21.3) COF 1799 1800 1801 1802 1827 1828 1829 1830 1947 1948 1949 1951 1953 1954 1955 1956 1957 1958 2023 2024 2066 2067 2068 2073 2074 2090 2091 2092|KMT2A/AFF1 KMT2A (11q23.3) AFF1 (4q21.3) TIC
Atlas Image
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 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.


Rawan Faramand ; Rawan Faramand

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

Atlas Genet Cytogenet Oncol Haematol. 2017-02-01

Online version: http://atlasgeneticsoncology.org/haematological/1051/t(4;11)(q21;q23)

Historical Card

1997-12-01 t(4;11)(q21;q23) KMT2A/AFF1 by  Jean-Loup Huret,Jean-Loup Huret 

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