{{Short description|Protein-coding gene in the species Homo sapiens}} {{cs1 config|name-list-style=vanc}} {{Infobox_gene}} '''AF4/FMR2 family member 1''' is a protein that in humans is encoded by the ''AFF1'' gene.<ref name="pmid7689231">{{cite journal | vauthors = Domer PH, Fakharzadeh SS, Chen CS, Jockel J, Johansen L, Silverman GA, Kersey JH, Korsmeyer SJ | title = Acute mixed-lineage leukemia t(4;11)(q21;q23) generates an MLL-AF4 fusion product | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 16 | pages = 7884–8 | date = August 1993 | pmid = 7689231 | pmc = 47247 | doi = 10.1073/pnas.90.16.7884 | bibcode = 1993PNAS...90.7884D | doi-access = free }}</ref><ref name="pmid1423625">{{cite journal | vauthors = Gu Y, Nakamura T, Alder H, Prasad R, Canaani O, Cimino G, Croce CM, Canaani E | title = The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene | journal = Cell | volume = 71 | issue = 4 | pages = 701–8 | date = November 1992 | pmid = 1423625 | doi = 10.1016/0092-8674(92)90603-A | s2cid = 6257922 }}</ref><ref name="pmid8353274">{{cite journal | vauthors = Chen CS, Hilden JM, Frestedt J, Domer PH, Moore R, Korsmeyer SJ, Kersey JH | title = The chromosome 4q21 gene (AF-4/FEL) is widely expressed in normal tissues and shows breakpoint diversity in t(4;11)(q21;q23) acute leukemia | journal = Blood | volume = 82 | issue = 4 | pages = 1080–5 | date = August 1993 | doi = 10.1182/blood.V82.4.1080.bloodjournal8241080 | pmid = 8353274 | doi-access = free }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: AFF1 AF4/FMR2 family, member 1| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=4299}}</ref> At its same location was a record for a separate '''PBM1''' gene, which has since been withdrawn and considered an alias. It was previously known as '''AF4''' (ALL1-fused gene from chromosome 4).<ref name="entrez" />
The gene is a member of the AF4/FMR2 (AFF) family, a group of nuclear transcriptional activators which encourage RNA elongation. It is a component of the super elongation complex.<ref name=Melko2011>{{cite journal | vauthors = Melko M, Douguet D, Bensaid M, Zongaro S, Verheggen C, Gecz J, Bardoni B | title = Functional characterization of the AFF (AF4/FMR2) family of RNA-binding proteins: insights into the molecular pathology of FRAXE intellectual disability | journal = Human Molecular Genetics | volume = 20 | issue = 10 | pages = 1873–85 | date = May 2011 | pmid = 21330300 | doi = 10.1093/hmg/ddr069 | doi-access = free }}</ref> The AFF1 protein, and to the same extent AFF4, has multiple functions but is primarily used to assemble the components of the super elongation complex by creating binding surfaces.<ref name=":2" /><ref name=":1" /> It is recognized as a proto-oncogene: chromosomal translocations associated with leukemia can fuse this gene with others like KMT2A, producing an uncontrolled activator protein.<ref name="pmid7689231"/> Translocation creates the fusion protein KMT2A-AFF1 which is the primary oncogenic fusion that sets up the pre-leukemic conditions responsible for driving acute lymphoblastic leukemia.<ref name=":3" />
== Function == AFF1 is a multi functional transcriptional regulator protein capable of promoting transcription elongation<ref>{{Cite journal |last1=Wang |first1=Donghai |last2=Yin |first2=Zhinang |last3=Wang |first3=Honghong |last4=Wang |first4=Liyuan |last5=Li |first5=Tianyu |last6=Xiao |first6=Ruijing |last7=Xie |first7=Ting |last8=Han |first8=Ruyi |last9=Dong |first9=Rui |last10=Liu |first10=Hudan |last11=Liang |first11=Kaiwei |last12=Qing |first12=Guoliang |date=2023-03-29 |title=The super elongation complex drives transcriptional addiction in MYCN-amplified neuroblastoma |journal=Science Advances |volume=9 |issue=13 |article-number=eadf0005 |doi=10.1126/sciadv.adf0005 |pmc=10058231 |pmid=36989355 |bibcode=2023SciA....9F...5W }}</ref> as well as assembling the super elongation complex. RNA Polymerase II synthesizes mRNA using the DNA template strand during the elongation step of transcription with the support of AFF1 and the super elongation complex. In this complex AFF1 brings with it the P-TEFb protein, which stimulates RNA Polymerase II into transitioning from promoter-proximal pausing to productive elongation. AFF1 also brings the ELL elongation factor enzyme which increases the catalytic rate of RNA Polymerase II transcription, helping produce rapid gene expression. In this way AFF1 acts as a scaffold protein by assembling and stabilizing the super elongation complex to promote efficient transcription elongation.<ref name=":2">{{Cite journal |last1=Zheng |first1=Bin |last2=Aoi |first2=Yuki |last3=Shah |first3=Avani P. |last4=Iwanaszko |first4=Marta |last5=Das |first5=Siddhartha |last6=Rendleman |first6=Emily J. |last7=Zha |first7=Didi |last8=Khan |first8=Nabiha |last9=Smith |first9=Edwin R. |last10=Shilatifard |first10=Ali |date=2021-02-01 |title=Acute perturbation strategies in interrogating RNA polymerase II elongation factor function in gene expression |url=http://genesdev.cshlp.org/content/35/3-4/273 |journal=Genes & Development |language=en |volume=35 |issue=3–4 |pages=273–285 |doi=10.1101/gad.346106.120 |issn=0890-9369 |pmc=7849361 |pmid=33446572}}</ref>
== Structure and bonding == '''<big>Gene</big>'''
The AFF1 gene has 23 exons and is located on the human chromosome 4 at q21 spanning approximately 206,028 base pairs long. 24 transcript variants have been identified.<ref>{{Cite web |title=AFF1 ALF transcription elongation factor 1 [Homo sapiens (human)] - Gene - NCBI |url=https://www.ncbi.nlm.nih.gov/gene/4299 |access-date=2026-04-20 |website=www.ncbi.nlm.nih.gov}}</ref> These variants arise through alternative splicing with each variant encoding distinct protein isoforms. These protein isoforms vary in shape and length with the most stable canonical structure being AFF1-201.<ref name=":0" />
'''<big>Isoforms</big>'''<gallery> File:AFF1-201.gif|Image of AFF1-201 that consists of 1210 amino acids File:AFF1-202.jpg|Image of AFF1-202 that consists of 1218 amino acids File:AFF1-206.jpg|Image of AFF1-206 that consists of 406 amino acids File:AFF1-207.jpg|Image of AFF1-207 that consists of 52 amino acids File:AFF1-208.jpg|Image of AFF1-208 that consists of 137 amino acids File:AFF1-210.jpg|Image of AFF1-210 that consists of 194 amino acids </gallery>'''<big>Protein</big>'''
The AFF1 protein consists of approximately 1210 amino acids and contains multiple regions for protein-protein interactions. Direct, one-on-one interactions have been shown experimentally with both MLLT3 and ARFRP1 proteins, while broader datasets suggest association with numerous additional factors similarly involved in transcriptional regulation.<ref name=":0">{{Cite web |title=UniProt |url=https://www.uniprot.org/uniprotkb/P51825/entry |access-date=2026-04-20 |website=UniProt |language=en}}</ref>
<gallery> File:AFF1-MLLT3 Interaction.jpg|This is an image of the AFF1-MLLT3 interaction File:AFF1-ARFIP1.jpg|This is an illustration of the AFF1 and ARFIP1 protein–protein interaction, one of two binary interactions observed through experimentation. </gallery>
== Role in disease == AFF family proteins like AFF1 are critical for the stability and function of the super elongation complex.<ref>{{Cite journal |last1=Liang |first1=Kaiwei |last2=Smith |first2=Edwin R. |last3=Aoi |first3=Yuki |last4=Stoltz |first4=Kristen L. |last5=Katagi |first5=Hiroaki |last6=Woodfin |first6=Ashley R. |last7=Rendleman |first7=Emily J. |last8=Marshall |first8=Stacy A. |last9=Murray |first9=David C. |last10=Wang |first10=Lu |last11=Ozark |first11=Patrick A. |last12=Mishra |first12=Rama K. |last13=Hashizume |first13=Rintaro |last14=Schiltz |first14=Gary E. |last15=Shilatifard |first15=Ali |date=October 2018 |title=Targeting Processive Transcription Elongation via SEC Disruption for MYC-Induced Cancer Therapy |journal=Cell |volume=175 |issue=3 |pages=766–779.e17 |doi=10.1016/j.cell.2018.09.027 |issn=0092-8674 |pmc=6422358 |pmid=30340042}}</ref> Chromosomal translocation with Histone-lysine N-methyltransferase 2A, also known as mixed-lineage leukemia 1 (MLL1), is associated with acute lymphoblastic leukemia. KMT2A–AFF1, or MLL-AFF1, is one of the fused proteins responsible for misregulation of transcription elongation.<ref>{{Cite journal |last1=Lin |first1=Chengqi |last2=Smith |first2=Edwin R. |last3=Takahashi |first3=Hidehisa |last4=Lai |first4=Ka Chun |last5=Martin-Brown |first5=Skylar |last6=Florens |first6=Laurence |last7=Washburn |first7=Michael P. |last8=Conaway |first8=Joan W. |last9=Conaway |first9=Ronald C. |last10=Shilatifard |first10=Ali |date=February 2010 |title=AFF4, a Component of the ELL/P-TEFb Elongation Complex and a Shared Subunit of MLL Chimeras, Can Link Transcription Elongation to Leukemia |journal=Molecular Cell |volume=37 |issue=3 |pages=429–437 |doi=10.1016/j.molcel.2010.01.026 |issn=1097-2765 |pmc=2872029 |pmid=20159561}}</ref> The most common translocations of these proteins are KMT2A-AFF1 and its reciprocal AFF1-KMT2A<ref>{{Cite journal |last1=Smith |first1=Edwin |last2=Lin |first2=Chengqi |last3=Shilatifard |first3=Ali |date=2011-04-01 |title=The super elongation complex (SEC) and MLL in development and disease |url=http://genesdev.cshlp.org/content/25/7/661 |journal=Genes & Development |language=en |volume=25 |issue=7 |pages=661–672 |doi=10.1101/gad.2015411 |issn=0890-9369 |pmc=3070929 |pmid=21460034}}</ref>, however AFF1-KMT2A is not the main driver of acute lymphoblastic leukemia. Although AFF1-KMT2A is capable of setting up pre-leukemic conditions, this reciprocal protein fusion later becomes dispensable. The canonical oncogenic protein fusion is KMT2A-AFF1 which has been shown through gene-knockdown experimentation.<ref name=":3">{{Cite journal |last1=Kumar |first1=Ashish R. |last2=Yao |first2=Qing |last3=Li |first3=Quanzhi |last4=Sam |first4=Thien A. |last5=Kersey |first5=John H. |date=2011-03-01 |title=t(4;11) leukemias display addiction to MLL-AF4 but not to AF4-MLL |journal=Leukemia Research |volume=35 |issue=3 |pages=305–309 |doi=10.1016/j.leukres.2010.08.011 |issn=0145-2126 |pmc=3011030 |pmid=20869771}}</ref>
The dangerous pre-leukemic state caused by the KMT2A-AFF1 fusion is dependent on age because this fusion can lead to the misregulation of transcription elongation in fetal and embryonic hematopoietic stem cells. In contrast, the same fusion when induced in adult mice caused less hematopoietic stem cell proliferation.<ref>{{Cite journal |last1=Calderón |first1=Ariana S. |last2=Ghazanfari |first2=Roshanak |last3=Masoumi |first3=Zahra |last4=Kharazi |first4=Shabnam |last5=Palo |first5=Sara |last6=Lang |first6=Stefan |last7=Žemaitis |first7=Kristijonas |last8=Eldeeb |first8=Mohamed |last9=Subramaniam |first9=Agatheeswaran |last10=Soneji |first10=Shamit |last11=Stam |first11=Ronald W. |last12=Bryder |first12=David |last13=Böiers |first13=Charlotta |date=July 2025 |title=Ontogeny-specific induction of the KMT2A::AFF1-fusion drives development of a distinct CD24 positive pre-leukemic state |journal=Leukemia |language=en |volume=39 |issue=9 |pages=2099–2111 |doi=10.1038/s41375-025-02665-9 |issn=1476-5551 |pmc=12380613 |pmid=40646135}}</ref> center|thumb|484x484px|KMT2A-AFF1 fusion causing a pre-leukemic state in fetal/embryonic mice while having a reduced effect on adult mice.
AFF1 is also implicated in the transcriptional regulation of HIV and other viruses because its role in the super elongation complex is exploitable, enhancing viral gene expression through transcription elongation. In order to hijack the super elongation complex, HIV produces the Tat protein to recruit P-TEFb which ends up significantly boosting viral gene expression.<ref name=":1">{{Cite journal |last1=Schulze-Gahmen |first1=Ursula |last2=Upton |first2=Heather |last3=Birnberg |first3=Andrew |last4=Bao |first4=Katherine |last5=Chou |first5=Seemay |last6=Krogan |first6=Nevan J |last7=Zhou |first7=Qiang |last8=Alber |first8=Tom |date=2013-03-05 |title=The AFF4 scaffold binds human P-TEFb adjacent to HIV Tat |journal=eLife |language=en |volume=2 |article-number=e00327 |doi=10.7554/eLife.00327 |doi-access=free |issn=2050-084X |pmc=3589825 |pmid=23471103}}</ref> Tat also has an affinity for super elongation complexes containing AFF1 and AFF4 proteins. AFF1 and AFF4 scaffolding proteins create more stable binding surface for both Tat and P-TEFb proteins, because AFF family proteins reshape the surface of P-TEFb when present in the super elongation complex.<ref name=":1" /><ref>{{Cite journal |last1=Sobhian |first1=Bijan |last2=Laguette |first2=Nadine |last3=Yatim |first3=Ahmad |last4=Nakamura |first4=Mirai |last5=Levy |first5=Yves |last6=Kiernan |first6=Rosemary |last7=Benkirane |first7=Monsef |date=May 2010 |title=HIV-1 Tat Assembles a Multifunctional Transcription Elongation Complex and Stably Associates with the 7SK snRNP |journal=Molecular Cell |volume=38 |issue=3 |pages=439–451 |doi=10.1016/j.molcel.2010.04.012 |issn=1097-2765 |pmc=3595998 |pmid=20471949}}</ref>
== References == {{reflist}}
== External links == * {{UCSC gene info|AFF1}}
== Further reading == {{refbegin | 2}} * {{cite journal | vauthors = Morrissey J, Tkachuk DC, Milatovich A, Francke U, Link M, Cleary ML | title = A serine/proline-rich protein is fused to HRX in t(4;11) acute leukemias | journal = Blood | volume = 81 | issue = 5 | pages = 1124–31 | date = March 1993 | pmid = 8443374 | doi = 10.1182/blood.V81.5.1124.1124| doi-access = free }} * {{cite journal | vauthors = Nakamura T, Alder H, Gu Y, Prasad R, Canaani O, Kamada N, Gale RP, Lange B, Crist WM, Nowell PC | title = Genes on chromosomes 4, 9, and 19 involved in 11q23 abnormalities in acute leukemia share sequence homology and/or common motifs | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 10 | pages = 4631–5 | date = May 1993 | pmid = 8506309 | pmc = 46566 | doi = 10.1073/pnas.90.10.4631 | bibcode = 1993PNAS...90.4631N | doi-access = free }} * {{cite journal | vauthors = Frestedt JL, Hilden JM, Kersey JH | title = AF4/FEL, a gene involved in infant leukemia: sequence variations, gene structure, and possible homology with a genomic sequence on 5q31 | journal = DNA and Cell Biology | volume = 15 | issue = 8 | pages = 669–78 | date = August 1996 | pmid = 8769569 | doi = 10.1089/dna.1996.15.669 }} * {{cite journal | vauthors = Nilson I, Reichel M, Ennas MG, Greim R, Knörr C, Siegler G, Greil J, Fey GH, Marschalek R | title = Exon/intron structure of the human AF-4 gene, a member of the AF-4/LAF-4/FMR-2 gene family coding for a nuclear protein with structural alterations in acute leukaemia | journal = British Journal of Haematology | volume = 98 | issue = 1 | pages = 157–69 | date = July 1997 | pmid = 9233580 | doi = 10.1046/j.1365-2141.1997.1522966.x | s2cid = 25176760 | doi-access = free }} * {{cite journal | vauthors = Megonigal MD, Rappaport EF, Jones DH, Kim CS, Nowell PC, Lange BJ, Felix CA | title = Panhandle PCR strategy to amplify MLL genomic breakpoints in treatment-related leukemias | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 21 | pages = 11583–8 | date = October 1997 | pmid = 9326653 | pmc = 23546 | doi = 10.1073/pnas.94.21.11583 | bibcode = 1997PNAS...9411583M | doi-access = free }} * {{cite journal | vauthors = Felix CA, Kim CS, Megonigal MD, Slater DJ, Jones DH, Spinner NB, Stump T, Hosler MR, Nowell PC, Lange BJ, Rappaport EF | title = Panhandle polymerase chain reaction amplifies MLL genomic translocation breakpoint involving unknown partner gene | journal = Blood | volume = 90 | issue = 12 | pages = 4679–86 | date = December 1997 | pmid = 9389682 | doi = 10.1182/blood.V90.12.4679| doi-access = free }} * {{cite journal | vauthors = Isnard P, Depetris D, Mattei MG, Ferrier P, Djabali M | title = cDNA cloning, expression and chromosomal localization of the murine AF-4 gene involved in human leukemia | journal = Mammalian Genome | volume = 9 | issue = 12 | pages = 1065–8 | date = December 1998 | pmid = 9880680 | doi = 10.1007/s003359900927 | s2cid = 29956410 }} * {{cite journal | vauthors = Felix CA, Hosler MR, Slater DJ, Megonigal MD, Lovett BD, Williams TM, Nowell PC, Spinner NB, Owens NL, Hoxie J, Croce CM, Lange BJ, Rappaport EF | title = Duplicated regions of AF-4 intron 4 at t(4;11) translocation breakpoints | journal = Molecular Diagnosis | volume = 4 | issue = 4 | pages = 269–83 | date = December 1999 | pmid = 10671636 | doi = 10.1016/S1084-8592(99)80002-2 }} * {{cite journal | vauthors = Reichel M, Gillert E, Breitenlohner I, Angermüller S, Fey GH, Marschalek R, Repp R, Greil J, Beck JD | title = Rapid isolation of chromosomal breakpoints from patients with t(4;11) acute lymphoblastic leukemia: implications for basic and clinical research | journal = Leukemia | volume = 15 | issue = 2 | pages = 286–8 | date = February 2001 | pmid = 11236948 | doi = 10.1038/sj.leu.2402018 | s2cid = 42706811 | doi-access = }} * {{cite journal | vauthors = Raffini LJ, Slater DJ, Rappaport EF, Lo Nigro L, Cheung NK, Biegel JA, Nowell PC, Lange BJ, Felix CA | title = Panhandle and reverse-panhandle PCR enable cloning of der(11) and der(other) genomic breakpoint junctions of MLL translocations and identify complex translocation of MLL, AF-4, and CDK6 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 7 | pages = 4568–73 | date = April 2002 | pmid = 11930009 | pmc = 123688 | doi = 10.1073/pnas.062066799 | bibcode = 2002PNAS...99.4568R | doi-access = free }} * {{cite journal | vauthors = Bertrand FE, Spengeman JD, Shah N, LeBien TW | title = B-cell development in the presence of the MLL/AF4 oncoprotein proceeds in the absence of HOX A7 and HOX A9 expression | journal = Leukemia | volume = 17 | issue = 12 | pages = 2454–9 | date = December 2003 | pmid = 14562113 | doi = 10.1038/sj.leu.2403178 | s2cid = 10639425 | doi-access = }} * {{cite journal | vauthors = Caslini C, Serna A, Rossi V, Introna M, Biondi A | title = Modulation of cell cycle by graded expression of MLL-AF4 fusion oncoprotein | journal = Leukemia | volume = 18 | issue = 6 | pages = 1064–71 | date = June 2004 | pmid = 14990976 | doi = 10.1038/sj.leu.2403321 | s2cid = 19189264 | doi-access = }} * {{cite journal | vauthors = Bursen A, Moritz S, Gaussmann A, Moritz S, Dingermann T, Marschalek R | title = Interaction of AF4 wild-type and AF4.MLL fusion protein with SIAH proteins: indication for t(4;11) pathobiology? | journal = Oncogene | volume = 23 | issue = 37 | pages = 6237–49 | date = August 2004 | pmid = 15221006 | doi = 10.1038/sj.onc.1207837 | s2cid = 9645787 | doi-access = free }} * {{cite journal | vauthors = Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, Meil A, Wojcik J, Legrain P, Gauthier JM | title = Functional proteomics mapping of a human signaling pathway | journal = Genome Research | volume = 14 | issue = 7 | pages = 1324–32 | date = July 2004 | pmid = 15231748 | pmc = 442148 | doi = 10.1101/gr.2334104 }} * {{cite journal | vauthors = Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP | title = Large-scale characterization of HeLa cell nuclear phosphoproteins | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 33 | pages = 12130–5 | date = August 2004 | pmid = 15302935 | pmc = 514446 | doi = 10.1073/pnas.0404720101 | bibcode = 2004PNAS..10112130B | doi-access = free }} * {{cite journal | vauthors = Xia ZB, Popovic R, Chen J, Theisler C, Stuart T, Santillan DA, Erfurth F, Diaz MO, Zeleznik-Le NJ | title = The MLL fusion gene, MLL-AF4, regulates cyclin-dependent kinase inhibitor CDKN1B (p27kip1) expression | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 39 | pages = 14028–33 | date = September 2005 | pmid = 16169901 | pmc = 1236570 | doi = 10.1073/pnas.0506464102 | doi-access = free }} 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