Gene Summary

Gene:AFF4; AF4/FMR2 family member 4
Aliases: MCEF, CHOPS, AF5Q31
Summary:The protein encoded by this gene belongs to the AF4 family of transcription factors involved in leukemia. It is a component of the positive transcription elongation factor b (P-TEFb) complex. A chromosomal translocation involving this gene and MLL gene on chromosome 11 is found in infant acute lymphoblastic leukemia with ins(5;11)(q31;q31q23). [provided by RefSeq, Oct 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:AF4/FMR2 family member 4
Source:NCBIAccessed: 01 September, 2019

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • DNA-Binding Proteins
  • HEK293 Cells
  • Base Sequence
  • Mutation
  • Homeodomain Proteins
  • Protein Binding
  • MLL
  • AFF2
  • Transcription Factors
  • Young Adult
  • Histones
  • Leukemia, Experimental
  • Transcriptional Elongation Factors
  • Leukaemia
  • Amino Acid Sequence
  • Spodoptera
  • Benzamides
  • Multiprotein Complexes
  • Mll protein, mouse
  • Repressor Proteins
  • Acute Lymphocytic Leukaemia
  • Cell Line
  • Positive Transcriptional Elongation Factor B
  • HSP70 Heat-Shock Proteins
  • HeLa Cells
  • HOXA10
  • KMT2A
  • Pyrimidines
  • Spermatozoa
  • myc Genes
  • Mllt3 protein, mouse
  • Infant
  • Translocation
  • Nuclear Proteins
  • Histone-Lysine N-Methyltransferase
  • Transcription
  • Chromosome 5
  • AFF4 (AF5q31)
  • Neoplastic Cell Transformation
  • Molecular Sequence Data
  • Chronic Myelogenous Leukemia
  • Apoptosis
  • Oncogene Fusion Proteins
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: AFF4 (cancer-related)

Liang K, Smith ER, Aoi Y, et al.
Targeting Processive Transcription Elongation via SEC Disruption for MYC-Induced Cancer Therapy.
Cell. 2018; 175(3):766-779.e17 [PubMed] Article available free on PMC after 18/10/2019 Related Publications
The super elongation complex (SEC) is required for robust and productive transcription through release of RNA polymerase II (Pol II) with its P-TEFb module and promoting transcriptional processivity with its ELL2 subunit. Malfunction of SEC contributes to multiple human diseases including cancer. Here, we identify peptidomimetic lead compounds, KL-1 and its structural homolog KL-2, which disrupt the interaction between the SEC scaffolding protein AFF4 and P-TEFb, resulting in impaired release of Pol II from promoter-proximal pause sites and a reduced average rate of processive transcription elongation. SEC is required for induction of heat-shock genes and treating cells with KL-1 and KL-2 attenuates the heat-shock response from Drosophila to human. SEC inhibition downregulates MYC and MYC-dependent transcriptional programs in mammalian cells and delays tumor progression in a mouse xenograft model of MYC-driven cancer, indicating that small-molecule disruptors of SEC could be used for targeted therapy of MYC-induced cancer.

Deng P, Wang J, Zhang X, et al.
AFF4 promotes tumorigenesis and tumor-initiation capacity of head and neck squamous cell carcinoma cells by regulating SOX2.
Carcinogenesis. 2018; 39(7):937-947 [PubMed] Article available free on PMC after 18/10/2019 Related Publications
Super elongation complex (SEC) controls gene transcription by releasing Pol II from pausing. Previous studies have shown that dysfunction of SEC was associated with multiple human cancers, such as leukemia and breast cancer. However, the role of SEC in head and neck squamous cell carcinoma (HNSCC) development remains largely unknown. In this study, we found expression of AF4/FMR2 family member 4 (AFF4), the core component of SEC, was upregulated dramatically in HNSCC cell lines and tumor tissues. By using siRNA-mediated depletion and overexpression of AFF4, we demonstrated AFF4 promoted proliferation, migration and invasion of HNSCC cells. Moreover, we found AFF4 enhanced the aldehyde dehydrogenase (ALDH) activity and sphere formatting activity and was required for the tumor-initiation capacity of stem-like cells in HNSCC cell lines. Mechanistically, we found the role of AFF4 in regulation of HNSCC cell behaviors was mainly mediated by sex-determining region Y box2 (SOX2), a critical regulator involved in development of several human cancers. SOX2 expression changed in parallel with AFF4 expression in response to depletion and overexpression of AFF4, respectively. More importantly, overexpression of SOX2 rescued the inhibited proliferation, migration, invasion and ALDH activity induced by knockdown of AFF4 in HNSCC cells, at least in part. Collectively, our findings indicate AFF4 may serve as a biomarker and a potential target of therapies for patients with HNSCC.

Lokken AA, Achille NJ, Chang MJ, et al.
Importance of a specific amino acid pairing for murine MLL leukemias driven by MLLT1/3 or AFF1/4.
Leuk Res. 2014; 38(11):1309-15 [PubMed] Article available free on PMC after 18/10/2019 Related Publications
Acute leukemias caused by translocations of the MLL gene at chromosome 11 band q23 (11q23) are characterized by a unique gene expression profile. More recently, data from several laboratories indicate that the most commonly encountered MLL fusion proteins, MLLT1, MLLT3, and AFF1 are found within a molecular complex that facilitates the elongation phase of mRNA transcription. Mutational analyses suggest that interaction between the MLLT1/3 proteins and AFF family proteins are required for experimental transformation of hematopoietic progenitor cells (HPCs). Here, we define a specific pairing of two amino acids that creates a salt bridge between MLLT1/3 and AFF proteins that is critically important for MLL-mediated transformation of HPCs. Our findings, coupled with the newly defined structure of MLLT3 in complex with AFF1, should facilitate the development of small molecules that block this amino acid interaction and interfere with the activity of the most common MLL oncoproteins.

Galbraith MD, Allen MA, Bensard CL, et al.
HIF1A employs CDK8-mediator to stimulate RNAPII elongation in response to hypoxia.
Cell. 2013; 153(6):1327-39 [PubMed] Article available free on PMC after 18/10/2019 Related Publications
The transcription factor HIF1A is a key mediator of the cellular response to hypoxia. Despite the importance of HIF1A in homeostasis and various pathologies, little is known about how it regulates RNA polymerase II (RNAPII). We report here that HIF1A employs a specific variant of the Mediator complex to stimulate RNAPII elongation. The Mediator-associated kinase CDK8, but not the paralog CDK19, is required for induction of many HIF1A target genes. HIF1A induces binding of CDK8-Mediator and the super elongation complex (SEC), containing AFF4 and CDK9, to alleviate RNAPII pausing. CDK8 is dispensable for HIF1A chromatin binding and histone acetylation, but it is essential for binding of SEC and RNAPII elongation. Global analysis of active RNAPII reveals that hypoxia-inducible genes are paused and active prior to their induction. Our results provide a mechanistic link between HIF1A and CDK8, two potent oncogenes, in the cellular response to hypoxia.

Luo Z, Lin C, Guest E, et al.
The super elongation complex family of RNA polymerase II elongation factors: gene target specificity and transcriptional output.
Mol Cell Biol. 2012; 32(13):2608-17 [PubMed] Article available free on PMC after 18/10/2019 Related Publications
The elongation stage of transcription is highly regulated in metazoans. We previously purified the AFF1- and AFF4-containing super elongation complex (SEC) as a major regulator of development and cancer pathogenesis. Here, we report the biochemical isolation of SEC-like 2 (SEC-L2) and SEC-like 3 (SEC-L3) containing AFF2 and AFF3 in association with P-TEFb, ENL/MLLT1, and AF9/MLLT3. The SEC family members demonstrate high levels of polymerase II (Pol II) C-terminal domain kinase activity; however, only SEC is required for the proper induction of the HSP70 gene upon stress. Genome-wide mRNA-Seq analyses demonstrated that SEC-L2 and SEC-L3 control the expression of different subsets of genes, while AFF4/SEC plays a more dominant role in rapid transcriptional induction in cells. MYC is one of the direct targets of AFF4/SEC, and SEC recruitment to the MYC gene regulates its expression in different cancer cells, including those in acute myeloid or lymphoid leukemia. These findings suggest that AFF4/SEC could be a potential therapeutic target for the treatment of leukemia or other cancers associated with MYC overexpression.

Nadarajan VS, Phan CL, Ang CH, et al.
Identification of copy number alterations by array comparative genomic hybridization in patients with late chronic or accelerated phase chronic myeloid leukemia treated with imatinib mesylate.
Int J Hematol. 2011; 93(4):465-473 [PubMed] Related Publications
The outcome of treating chronic myeloid leukemia (CML) with imatinib mesylate (IM) is inferior when therapy is commenced in late chronic or accelerated phase as compared to early chronic phase. This may be attributed to additional genomic alterations that accumulate during disease progression. We sought to identify such lesions in patients showing suboptimal response to IM by performing array-CGH analysis on 39 sequential samples from 15 CML patients. Seventy-four cumulative copy number alterations (CNAs) consisting of 35 losses and 39 gains were identified. Alterations flanking the ABL1 and BCR genes on chromosomes 9 and 22, respectively, were the most common identified lesions with 5 patients losing variable portions of 9q34.11 proximal to ABL1. Losses involving 1p36, 5q31, 17q25, Y and gains of 3q21, 8q24, 22q11, Xp11 were among other recurrent lesions identified. Aberrations were also observed in individual patients, involving regions containing known leukemia-associated genes; CDKN2A/2B, IKZF1, RB1, TLX1, AFF4. CML patients in late stages of their disease, harbor pre-existing and evolving sub-microscopic CNAs that may influence disease progression and IM response.

Monroe SC, Jo SY, Sanders DS, et al.
MLL-AF9 and MLL-ENL alter the dynamic association of transcriptional regulators with genes critical for leukemia.
Exp Hematol. 2011; 39(1):77-86.e1-5 [PubMed] Article available free on PMC after 18/10/2019 Related Publications
OBJECTIVE: The aim of this study was to better understand how mixed lineage leukemia (MLL) fusion proteins deregulate the expression of genes critical for leukemia.
MATERIALS AND METHODS: The transforming domain of one of the most common MLL fusion partners, AF9, was immunopurified after expression in myeloblastic M1 cells, and associating proteins were identified by mass spectrometric analysis. Chromatin immunoprecipitation followed by quantitative polymerase chain reaction was used to determine how binding of associating proteins compare across Hoxa9 and Meis1 in cell lines with and without MLL fusion proteins and how binding is altered during gene down-regulation and differentiation.
RESULTS: Consistent with earlier purifications of ENL and AF4 from 293 cells, the 90 amino acid C-terminal domain of AF9 associates with many other MLL translocation partners including Enl, Af4, Laf4, Af5q31, Ell, and Af10. This complex, termed elongation assisting proteins (EAPs), also contains the RNA polymerase II C-terminal domain kinase Cdk9/Cyclin T1/T2 (pTEFb) and the histone H3 lysine 79 methyltransferase Dot1L. Myeloid cells transformed by MLL fusions show higher levels and a broader distribution of EAP components at genes critical for leukemia. Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented.
CONCLUSIONS: The findings suggest that MLL fusion proteins deregulate genes critical for leukemia by excessive recruitment and impaired dissociation of EAP from target loci.

Fromm G, Adelman K
Taking MLL through the MudPIT: identification of novel complexes that bring together MLL-fusion proteins and transcription elongation factors.
Mol Cell. 2010; 37(4):449-50 [PubMed] Related Publications
Recently in Molecular Cell, Lin et al. (2010) showed that multiple MLL-fusion proteins implicated in mixed-lineage leukemia (MLL) associate with AFF4, ELLs, and the positive transcription elongation factor P-TEFb, providing evidence that the dysregulated gene expression in MLL patients is due to aberrant transcription elongation.

Lin C, Smith ER, Takahashi H, et al.
AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia.
Mol Cell. 2010; 37(3):429-37 [PubMed] Article available free on PMC after 18/10/2019 Related Publications
Chromosomal translocations involving the MLL gene are associated with infant acute lymphoblastic and mixed lineage leukemia. There are a large number of translocation partners of MLL that share very little sequence or seemingly functional similarities; however, their translocations into MLL result in the pathogenesis of leukemia. To define the molecular reason why these translocations result in the pathogenesis of leukemia, we purified several of the commonly occurring MLL chimeras. We have identified super elongation complex (SEC) associated with all chimeras purified. SEC includes ELL, P-TEFb, AFF4, and several other factors. AFF4 is required for SEC stability and proper transcription by poised RNA polymerase II in metazoans. Knockdown of AFF4 in leukemic cells shows reduction in MLL chimera target gene expression, suggesting that AFF4/SEC could be a key regulator in the pathogenesis of leukemia through many of the MLL partners.

Urano A, Endoh M, Wada T, et al.
Infertility with defective spermiogenesis in mice lacking AF5q31, the target of chromosomal translocation in human infant leukemia.
Mol Cell Biol. 2005; 25(15):6834-45 [PubMed] Article available free on PMC after 18/10/2019 Related Publications
AF5q31 (also called MCEF) was identified by its involvement in chromosomal translocation with the gene MLL (mixed lineage leukemia), which is associated with infant acute lymphoblastic leukemia. Several potential roles have been proposed for AF5q31 and other family genes, but the specific requirements of AF5q31 during development remain unclear. Here, we show that AF5q31 is essential for spermatogenesis. Although most AF5q31-deficient mice died in utero and neonatally with impaired embryonic development and shrunken alveoli, respectively, 13% of AF5q31-deficient mice thrived as wild-type mice did. However, the male mice were sterile with azoospermia. Histological examinations revealed the arrest of germ cell development at the stage of spermiogenesis, and virtually no spermatozoa were seen in the epididymis. AF5q31 was found to be preferentially expressed in Sertoli cells. Furthermore, mutant mice displayed severely impaired expression of protamine 1, protamine 2, and transition protein 2, which are indispensable to compact the haploid genome within the sperm head, and an increase of apoptotic cells in seminiferous tubules. Thus, AF5q31 seems to function as a transcriptional regulator in testicular somatic cells and is essential for male germ cell differentiation and survival. These results may have clinical implications in the understanding of human male infertility.

Kamakari S, Roussou A, Jefferson A, et al.
Structural analysis and expression profile of a novel gene on chromosome 5q23 encoding a Golgi-associated protein with six splice variants, and involved within the 5q deletion of a Ph(-) CML patient.
Leuk Res. 2005; 29(1):17-31 [PubMed] Related Publications
We have identified a novel gene, upstream of the cytokine gene cluster region in 5q23-31, residing within one of the most common deleted segments associated with MDS. The novel gene exhibits significant alternative splicing generating at least six splice variants encoding four putative proline-rich protein isoforms, one of which is Golgi-associated. The gene is ubiquitously expressed and conserved among species with the C. elegans homologue being the most interesting, since it resides within an operon with two other genes, phospholipase D and dishevelled, a member of the Wnt pathway, suggesting a functional association. In addition, the novel gene and other key regulatory genes of the region, such IL3, Ril, AF5q31 and TCF-1, were found to be deleted in an atypical CML case, thus underscoring the significance of this subregion in the leukemogenesis process.

Deveney R, Chervinsky DS, Jani-Sait SN, et al.
Insertion of MLL sequences into chromosome band 5q31 results in an MLL-AF5Q31 fusion and is a rare but recurrent abnormality associated with infant leukemia.
Genes Chromosomes Cancer. 2003; 37(3):326-31 [PubMed] Related Publications
MLL gene rearrangements leading to production of MLL fusion proteins are commonly detected in infant leukemia patients; the most common MLL fusion associated with infant leukemia is the MLL-AF4 fusion. A single case of chromosomal rearrangement leading to production of an MLL fusion with AF5Q31, a gene structurally similar to AF4, has been detected recently in the malignant cells of an infant leukemia patient. We have identified a second case of MLL-AF5Q31 fusion, arising from an insertion of MLL sequences into chromosome 5, also in an infant leukemia patient. Because MLL and AF5Q31 are transcribed in opposite orientations, a simple balanced chromosomal translocation cannot produce a fusion protein, and complex chromosomal rearrangements such as insertions and inversions are required to produce an MLL-AF5Q31 fusion protein. This report demonstrates that chromosomal insertion of MLL sequences is a rare but recurrent abnormality associated with infant leukemia.

Hiwatari M, Taki T, Taketani T, et al.
Fusion of an AF4-related gene, LAF4, to MLL in childhood acute lymphoblastic leukemia with t(2;11)(q11;q23).
Oncogene. 2003; 22(18):2851-5 [PubMed] Related Publications
We showed that the LAF4 gene on 2q11.2-12 was fused to the MLL gene on 11q23 in a pediatric patient with CD10 positive acute lymphoblastic leukemia (ALL) having t(2;11)(q11;q23). The LAF4 gene, which encodes a lymphoid nuclear protein of 1227 amino acids with transactivation potential, is thought to have a role in early lymphoid development. The LAF4 protein was homologous to AF4 and AF5q31 proteins that are fused to MLL in infant early pre-B ALL and the breakpoint of LAF4 was located within the region homologous to the transactivation domain of AF4 and AF5q31. Expression of the 8.5-kb LAF4 transcript was detected in the adult heart, brain, and placenta and in the fetal brain. LAF4 expression was found to be higher in ALL cell lines than in AML and Epstein-Barr virus-transformed B-lymphocyte cell lines. These findings suggest that LAF4, AF4 and AF5q31 might define a new family particularly involved in the pathogenesis of 11q23-associated ALL.

Imamura T, Morimoto A, Ikushima S, et al.
A novel infant acute lymphoblastic leukemia cell line with MLL-AF5q31 fusion transcript.
Leukemia. 2002; 16(11):2302-8 [PubMed] Related Publications
Infant acute lymphoblastic leukemia (ALL) is characterized by the presence of the proB phenotype (CD10(-)/CD19(+)), poor prognosis and frequent rearrangement of the mixed lineage leukemia (MLL) gene. The most frequent rearrangement is t(4;11)(q21;q23), the role of whose product, the MLL-AF4 fusion transcript, has been extensively studied in leukemogenesis. In a cell line of infant leukemia with MLL rearrangement denoted KP-L-RY, panhandle PCR amplification of cDNA revealed the presence of a fusion transcript, MLL-AF5q31, indicating that AF5q31 is also a partner gene of MLL. In this fusion transcript the MLL exon 6 is fused in frame to the 5' side of the putative transactivation domain of AF5q31. The AF5q31 protein is a member of the AF4/LAF4/FMR2-related family of proteins, which have been suggested to play a role in hematopoietic cell growth and differentiation. The MLL-AF5q31 fusion transcript, although probably rare, appears to be associated with the pathogenesis of infant ALL like MLL-AF4. Co-expression of HoxA9 and Meis1 genes in the KP-L-RY cell line indicated possible functional similarity between MLL-AF4 and MLL-AF5q31. Further understanding of the function of AF5q31 as well as the specific leukemogenic mechanism of MLL-AF5q31 awaits future studies.

von Bergh AR, Beverloo HB, Rombout P, et al.
LAF4, an AF4-related gene, is fused to MLL in infant acute lymphoblastic leukemia.
Genes Chromosomes Cancer. 2002; 35(1):92-6 [PubMed] Related Publications
Infant acute lymphoblastic leukemia (ALL) with MLL gene rearrangements is characterized by a proB phenotype and a poor clinical outcome. We analyzed an infant proB ALL with t(2;11)(p15;p14) and an MLL rearrangement on Southern blot analysis. Rapid amplification of cDNA ends-polymerase chain reaction (PCR) and reverse transcriptase-PCR identified the LAF4 gene mapped on chromosome region 2q11.2-q12 as a fusion partner of the MLL gene. The LAF4 gene was identified previously by its high sequence homology to the AF4 protein and encodes a protein of 1,227 amino acids. The t(4;11)(q21;q23), creating the MLL-AF4 chimeric transcripts, is the predominant 11q23 chromosome translocation in infant ALL and is associated with an extremely poor prognosis. Our findings further suggest that fusion of MLL to one of the AF4 family members (AF4/LAF4/AF5Q31) might determine a proB-cell phenotype in infant leukemia.

Estable MC, Naghavi MH, Kato H, et al.
MCEF, the newest member of the AF4 family of transcription factors involved in leukemia, is a positive transcription elongation factor-b-associated protein.
J Biomed Sci. 2002 May-Jun; 9(3):234-45 [PubMed] Related Publications
Positive transcription elongation factor-b (P-TEFb) contains CDK9 and cyclin T(1). P-TEFb was affinity purified from a stably transfected cell line that expresses epitope-tagged CDK9, and proteins that appeared to be specifically bound were sequenced. In addition to CDK9, previously identified isoforms of cyclin T (including T(1), T(2A) and T(2B)), HSP90 and CDC37, this analysis identified a novel protein named MCEF. Cloning of its cognate cDNA revealed that MCEF is the newest member of the AF4 family of transcription factors involved in acute lymphoblastic leukemia. MCEF RNA was expressed in all human tissues examined, and antisera directed against recombinant MCEF specifically immunoprecipitated P-TEFb. Ectopic expression of MCEF did not activate HIV-1 replication, and tethering of MCEF to a promoter did not activate transcription.

Taki T, Kano H, Taniwaki M, et al.
AF5q31, a newly identified AF4-related gene, is fused to MLL in infant acute lymphoblastic leukemia with ins(5;11)(q31;q13q23).
Proc Natl Acad Sci U S A. 1999; 96(25):14535-40 [PubMed] Article available free on PMC after 18/10/2019 Related Publications
Infant acute lymphoblastic leukemia (ALL) with MLL gene rearrangements is characterized by early pre-B phenotype (CD10(-)/CD19(+)) and poor treatment outcome. The t(4;11), creating MLL-AF4 chimeric transcripts, is the predominant 11q23 chromosome translocation in infant ALL and is associated with extremely poor prognosis as compared with other 11q23 translocations. We analyzed an infant early preB ALL with ins(5;11)(q31;q13q23) and identified the AF5q31 gene on chromosome 5q31 as a fusion partner of the MLL gene. The AF5q31 gene, which encoded a protein of 1,163 aa, was located in the vicinity of the cytokine cluster region of chromosome 5q31 and contained at least 16 exons. The AF5q31 gene was expressed in fetal heart, lung, and brain at relatively high levels and fetal liver at a low level, but the expression in these tissues decreased in adults. The AF5q31 protein was homologous to AF4-related proteins, including AF4, LAF4, and FMR2. The AF5q31 and AF4 proteins had three homologous regions, including the transactivation domain of AF4, and the breakpoint of AF5q31 was located within the region homologous to the transactivation domain of AF4. Furthermore, the clinical features of this patient with the MLL-AF5q31 fusion transcript, characterized by the early pre-B phenotype (CD10(-)/CD19(+)) and poor outcome, were similar to those of patients having MLL-AF4 chimeric transcripts. These findings suggest that AF5q31 and AF4 might define a new family particularly involved in the pathogenesis of 11q23-associated-ALL.

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Cite this page: Cotterill SJ. AF5Q31, Cancer Genetics Web: Accessed:

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