The human AF9/MLLT3 gene is a common fusion partner for the MLL gene in translocations t(9;11)(p22;q23) associated with acute myeloid leukemia and acute lymphocytic leukemia. The exact function of the gene is still unknown, although a mouse knock-out model points to a role as a controller of embryo patterning. We report the case of a constitutional translocation t(4;9)(q35;p22) disrupting the AF9/MLLT3 gene in a girl with neuromotor development delay, cerebellar ataxia and epilepsy. Array-CGH analysis at 1 Mbase resolution did not reveal any additional deletions/duplications. We hypothesize a loss-of-function mutation of the AF9/MLLT3 gene, and a possible role for the FAT gene on chromosome 4, in the genesis of the proband's severe neurological phenotype.
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Structural studies of intrinsically disordered MLL-fusion protein AF9 in complex with peptidomimetic inhibitors.
Protein Sci
June 2024
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
AF9 (MLLT3) and its paralog ENL(MLLT1) are members of the YEATS family of proteins with important role in transcriptional and epigenetic regulatory complexes. These proteins are two common MLL fusion partners in MLL-rearranged leukemias. The oncofusion proteins MLL-AF9/ENL recruit multiple binding partners, including the histone methyltransferase DOT1L, leading to aberrant transcriptional activation and enhancing the expression of a characteristic set of genes that drive leukemogenesis.
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Exp Hematol
August 2023
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI. Electronic address:
Recent studies have uncovered similarities and differences between 2 highly homologous epigenetic reading proteins, namely, ENL (MLLT1) and AF9 (MLLT3) with therapeutic implications. The importance of these proteins has traditionally been exemplified by their involvement in chromosomal translocations with the mixed-lineage leukemia gene (MLL; aka KMT2a). MLL rearrangements occur in a subset of acute leukemias and generate potent oncogenic MLL-fusion proteins that impact epigenetic and transcriptional regulation.
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Int J Mol Sci
October 2021
Department of Experimental and Clinical Medicine, University Magna Græcia, 88100 Catanzaro, Italy.
Leukemias derived from the MLL-AF9 rearrangement rely on dysfunctional transcriptional networks. ZNF521, a transcription co-factor implicated in the control of hematopoiesis, has been proposed to sustain leukemic transformation in collaboration with other oncogenes. Here, we demonstrate that ZNF521 mRNA levels correlate with specific genetic aberrations: in particular, the highest expression is observed in AMLs bearing MLL rearrangements, while the lowest is detected in AMLs with FLT3-ITD, NPM1, or CEBPα double mutations.
View Article and Find Full Text PDFThe Intrinsically Disordered Proteins MLLT3 (AF9) and MLLT1 (ENL) - Multimodal Transcriptional Switches With Roles in Normal Hematopoiesis, MLL Fusion Leukemia, and Kidney Cancer.
J Mol Biol
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Dept. of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22903, United States; Dept. of Chemistry, University of Virginia, Charlottesville, VA 22904, United States. Electronic address:
AF9 (MLLT3) and ENL (MLLT1) are members of the YEATS family (named after the five proteins first shown to contain this domain: Yaf9, ENL, AF9, Taf14, Sas5) defined by the presence of a YEATS domain. The YEATS domain is an epigenetic reader that binds to acetylated and crotonylated lysines, unlike the bromodomain which can only bind to acetylated lysines. All members of this family have been shown to be components of various complexes with roles in chromatin remodeling, histone modification, histone variant deposition, and transcriptional regulation.
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Blood Cancer Discov
September 2020
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia.
MLL is a target of chromosomal translocations in acute leukemias with poor prognosis. The common MLL fusion partner AF9 (MLLT3) can directly bind to AF4, DOT1L, BCOR, and CBX8. To delineate the relevance of BCOR and CBX8 binding to MLL-AF9 for leukemogenesis, here we determine protein structures of AF9 complexes with CBX8 and BCOR, and show that binding of all four partners to AF9 is mutually exclusive.
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