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Gene Review

AFF1  -  AF4/FMR2 family, member 1

Homo sapiens

Synonyms: AF-4, AF4, AF4/FMR2 family member 1, ALL1-fused gene from chromosome 4 protein, FEL, ...
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Disease relevance of AFF1

  • The human AF4 (ALL-1 fused gene on chromosome 4) gene (4q11) is recurrently involved in reciprocal translocations to the MLL (mixed lineage leukemia) gene (11q23), correlated with high-risk acute lymphoblastic leukemia (ALL) in infants and early childhood [1].
  • The AF4 protein interacts with the product of another gene, AF9, which is also fused to MLL in acute leukemias [2].
  • Transfection of leukemic cells with MLL-AF4 siRNAs reduces leukemia-associated morbidity and mortality in SCID mice that received a xenotransplant, suggesting that MLL-AF4 depletion negatively affects leukemia-initiating cells [3].
  • As concerning studies on minimal residual disease, data on PCR monitoring of the ALL1/AF4 fusion transcript, resulting from the t(4;11) translocation, show the clinical relevance of this molecular test in predicting outcome and, as a consequence, in designing individual post-remission therapies [4].
  • A set of recombinant phage carrying genomic fragments for the coding region and flanking sequences of the AF-4 gene were isolated [5].

Psychiatry related information on AFF1


High impact information on AFF1


Biological context of AFF1

  • We cloned and sequenced cDNAs derived from transcripts of the AF-4 and AF-9 genes involved in the most common chromosome abnormalities, t(4:11)(q21:q23) and t(9:11)(p22:q23), respectively [10].
  • To further evaluate the 4q21 gene and its role in t(4;11) acute leukemia, we have cloned a 38-kb genomic region and mapped exons of the AF-4 gene [11].
  • We provide evidence that this peptide is able to inhibit the proliferation of leukemia cells with t(4;11) chromosomal translocations expressing MLL-AF4 fusion genes [2].
  • The synthetic peptide PFWT disrupts AF4-AF9 protein complexes and induces apoptosis in t(4;11) leukemia cells [2].
  • Overexpression of MLL-AF4 does not lead to increased proliferation in either cell line, but rather, cell growth was slowed compared with similar cell lines inducibly expressing truncated MLL [9].

Anatomical context of AFF1

  • The AF-4 gene was expressed in all cell lines as a major and a minor transcript [11].
  • B-cell development in the presence of the MLL/AF4 oncoprotein proceeds in the absence of HOX A7 and HOX A9 expression [12].
  • We have previously established a novel MLL/AF4-positive cell line, B-lineage 3 (BLIN-3), which retains several features of normal B-lineage development (functional Ig gene rearrangement and apoptotic sensitivity to stromal cell withdrawal) not generally observed in infant ALL [12].
  • No evidence for MLL/AF4 expression in normal cord blood samples [13].
  • Young Mll-AF4 mice had lymphoid and myeloid deregulation manifest by increased lymphoid and myeloid cells in hematopoietic organs [14].

Associations of AFF1 with chemical compounds

  • FEL contains guanosine triphosphate-binding and nuclear localization consensus sequences and uses one of two possible 5' exons encoding the first 12 or 5 amino acids [15].
  • By varying the concentration of tetracycline in growth media, we found that increasing levels of MLL-AF4 expression result in a progressive decrease in growth rate and fraction of S phase cells, paralleled by an increase in percentage of cells expressing CD11b [16].
  • Cleavage of DNA substrates containing the normal homologues of the MLL and AF-4 translocation breakpoints was examined in vitro upon incubation with human DNA topoisomerase IIalpha and etoposide, etoposide catechol, etoposide quinone, or dactinomycin [17].
  • The expression level of MLL-AF4 fusion protein was not reduced by 17-AAG in human leukemia cells [18].
  • An H. pylori VacA-deficient mutant, AF4(vacA::kan), was cultured in significantly lower numbers from AGS cells after 24 h incubation with gentamicin added to the culture medium than were the type I wild-type strain AF4 (P<0.03) and an isogenic cagA mutant (P<0.01) [19].

Physical interactions of AFF1

  • In two-hybrid studies, ENL interacted with AF4 and AF5q31 as well as with a fragment of AF10 [20].

Other interactions of AFF1


Analytical, diagnostic and therapeutic context of AFF1

  • Using primer sets derived from ALL-1 and AF4 cDNAs by reverse transcription-polymerase chain reaction (RT-PCR), we were able to amplify the breakpoint sites of the fusion transcript of all 15 ALL cases with karyotypic or molecular evidence of the t(4;11) [23].
  • Using Western blotting analysis, we demonstrated that the AF4 gene encodes proteins with apparent molecular weight of 125 and 145 kD [24].
  • A 45-kD protein coprecipitated with AF4 protein in immunoprecipitation [24].
  • ALL1 gene breakpoint distribution was determined by Southern blot hybridization and/or reverse transcription-PCR of the ALL1/AF4 fusion cDNA in 70 patients [25].
  • We now use microarray analysis to identify patterns of gene expression in BLIN-3 that may modulate MLL/AF4 oncogenesis and contribute to the retention of normal B-lineage developmental characteristics [12].


  1. Interaction of AF4 wild-type and AF4.MLL fusion protein with SIAH proteins: indication for t(4;11) pathobiology? Bursen, A., Moritz, S., Gaussmann, A., Moritz, S., Dingermann, T., Marschalek, R. Oncogene (2004) [Pubmed]
  2. The synthetic peptide PFWT disrupts AF4-AF9 protein complexes and induces apoptosis in t(4;11) leukemia cells. Srinivasan, R.S., Nesbit, J.B., Marrero, L., Erfurth, F., LaRussa, V.F., Hemenway, C.S. Leukemia (2004) [Pubmed]
  3. Targeting MLL-AF4 with short interfering RNAs inhibits clonogenicity and engraftment of t(4;11)-positive human leukemic cells. Thomas, M., Gessner, A., Vornlocher, H.P., Hadwiger, P., Greil, J., Heidenreich, O. Blood (2005) [Pubmed]
  4. ALL1 gene alterations in acute leukemia: biological and clinical aspects. Cimino, G., Rapanotti, M.C., Sprovieri, T., Elia, L. Haematologica (1998) [Pubmed]
  5. 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. Nilson, I., Reichel, M., Ennas, M.G., Greim, R., Knörr, C., Siegler, G., Greil, J., Fey, G.H., Marschalek, R. Br. J. Haematol. (1997) [Pubmed]
  6. Retrospective comparison of qualitative and quantitative reverse transcriptase polymerase chain reaction in diagnosing and monitoring the ALL1-AF4 fusion transcript in patients with acute lymphoblastic leukaemia. Elia, L., Gottardi, E., Floriddia, G., Grillo, R., Ciambelli, F., Luciani, M., Chiusolo, P., Invernizzi, R., Meloni, G., Foà, R., Saglio, G., Cimino, G. Leukemia (2004) [Pubmed]
  7. Lilliputian: an AF4/FMR2-related protein that controls cell identity and cell growth. Wittwer, F., van der Straten, A., Keleman, K., Dickson, B.J., Hafen, E. Development (2001) [Pubmed]
  8. Identification of FMR2, a novel gene associated with the FRAXE CCG repeat and CpG island. Gu, Y., Shen, Y., Gibbs, R.A., Nelson, D.L. Nat. Genet. (1996) [Pubmed]
  9. The MLL fusion gene, MLL-AF4, regulates cyclin-dependent kinase inhibitor CDKN1B (p27kip1) expression. Xia, Z.B., Popovic, R., Chen, J., Theisler, C., Stuart, T., Santillan, D.A., Erfurth, F., Diaz, M.O., Zeleznik-Le, N.J. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  10. Genes on chromosomes 4, 9, and 19 involved in 11q23 abnormalities in acute leukemia share sequence homology and/or common motifs. Nakamura, T., Alder, H., Gu, Y., Prasad, R., Canaani, O., Kamada, N., Gale, R.P., Lange, B., Crist, W.M., Nowell, P.C. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  11. 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. Chen, C.S., Hilden, J.M., Frestedt, J., Domer, P.H., Moore, R., Korsmeyer, S.J., Kersey, J.H. Blood (1993) [Pubmed]
  12. B-cell development in the presence of the MLL/AF4 oncoprotein proceeds in the absence of HOX A7 and HOX A9 expression. Bertrand, F.E., Spengeman, J.D., Shah, N., LeBien, T.W. Leukemia (2003) [Pubmed]
  13. No evidence for MLL/AF4 expression in normal cord blood samples. Trka, J., Zuna, J., Hrusák, O., Michalová, K., Muziková, K., Kalinová, M., Horák, J., Starý, J. Blood (1999) [Pubmed]
  14. A murine Mll-AF4 knock-in model results in lymphoid and myeloid deregulation and hematologic malignancy. Chen, W., Li, Q., Hudson, W.A., Kumar, A., Kirchhof, N., Kersey, J.H. Blood (2006) [Pubmed]
  15. A serine/proline-rich protein is fused to HRX in t(4;11) acute leukemias. Morrissey, J., Tkachuk, D.C., Milatovich, A., Francke, U., Link, M., Cleary, M.L. Blood (1993) [Pubmed]
  16. Modulation of cell cycle by graded expression of MLL-AF4 fusion oncoprotein. Caslini, C., Serna, A., Rossi, V., Introna, M., Biondi, A. Leukemia (2004) [Pubmed]
  17. Near-precise interchromosomal recombination and functional DNA topoisomerase II cleavage sites at MLL and AF-4 genomic breakpoints in treatment-related acute lymphoblastic leukemia with t(4;11) translocation. Lovett, B.D., Lo Nigro, L., Rappaport, E.F., Blair, I.A., Osheroff, N., Zheng, N., Megonigal, M.D., Williams, W.R., Nowell, P.C., Felix, C.A. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  18. FLT3 expressing leukemias are selectively sensitive to inhibitors of the molecular chaperone heat shock protein 90 through destabilization of signal transduction-associated kinases. Yao, Q., Nishiuchi, R., Li, Q., Kumar, A.R., Hudson, W.A., Kersey, J.H. Clin. Cancer Res. (2003) [Pubmed]
  19. Reduced intracellular survival of Helicobacter pylori vacA mutants in comparison with their wild-types indicates the role of VacA in pathogenesis. Petersen, A.M., Sørensen, K., Blom, J., Krogfelt, K.A. FEMS Immunol. Med. Microbiol. (2001) [Pubmed]
  20. The eleven-nineteen-leukemia protein ENL connects nuclear MLL fusion partners with chromatin. Zeisig, D.T., Bittner, C.B., Zeisig, B.B., García-Cuéllar, M.P., Hess, J.L., Slany, R.K. Oncogene (2005) [Pubmed]
  21. Simultaneous localization of MLL, AF4 and ENL genes in interphase nuclei by 3D-FISH: MLL translocation revisited. Gué, M., Sun, J.S., Boudier, T. BMC Cancer (2006) [Pubmed]
  22. LAF4, an AF4-related gene, is fused to MLL in infant acute lymphoblastic leukemia. von Bergh, A.R., Beverloo, H.B., Rombout, P., van Wering, E.R., van Weel, M.H., Beverstock, G.C., Kluin, P.M., Slater, R.M., Schuuring, E. Genes Chromosomes Cancer (2002) [Pubmed]
  23. Detection of ALL-1/AF4 fusion transcript by reverse transcription-polymerase chain reaction for diagnosis and monitoring of acute leukemias with the t(4;11) translocation. Biondi, A., Rambaldi, A., Rossi, V., Elia, L., Caslini, C., Basso, G., Battista, R., Barbui, T., Mandelli, F., Masera, G. Blood (1993) [Pubmed]
  24. AF4 encodes a ubiquitous protein that in both native and MLL-AF4 fusion types localizes to subnuclear compartments. Li, Q., Frestedt, J.L., Kersey, J.H. Blood (1998) [Pubmed]
  25. Infant acute leukemias show the same biased distribution of ALL1 gene breaks as topoisomerase II related secondary acute leukemias. Cimino, G., Rapanotti, M.C., Biondi, A., Elia, L., Lo Coco, F., Price, C., Rossi, V., Rivolta, A., Canaani, E., Croce, C.M., Mandelli, F., Greaves, M. Cancer Res. (1997) [Pubmed]
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