Abstract
In the hematopoietic system, menin was found to interact with MLL, a large protein encoded by the mixed linage leukemia gene that acts as a histone H3 methyltransferase. The MLL gene is a recurrent target for translocations in both acute myeloid and acute lymphoid leukemias. MLL gene rearrangements involve a variety of translocation partners, giving rise to MLL fusion proteins whose transforming ability is mediated through upregulated expression of Homeobox (Hox) genes as well as other targets. Recent work indicates that menin is an essential partner of MLL fusion proteins in leukemic cells and that it regulates normal hematopoiesis. In the absence of menin, steady-state hematopoiesis is largely preserved; however, menin-deficient hematopoietic stem cells are markedly deficient in situations of hematopoietic stress, such as during recovery after bone marrow transplantation. In leukemias driven by MLL fusion proteins, menin is essential for transformation and growth of the malignant cells. Thus, menin-MLL interactions represent a promising therapeutic target in leukemias with MLL rearrangements.
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References
Felix CA. Secondary leukemias induced by topoisomerase-targeted drugs. Biochim Biophys Acta 1998; 1400:233–55.
Yokoyama A, Kitabayashi I, Ayton PM et al. Leukemia proto-oncoprotein MLL is proteolytically processed into 2 fragments with opposite transcriptional properties. Blood 2002; 100:3710–8.
Nakamura T, Mod T, Tada S et al. ALL-1 is a histone methyltransferase that assemblesa supercomplex of proteins involved in transcriptional regulation. Mol Cell 2002; 10:1119–28.
Birke M, Schreiner S, Garcia-Cuellar MP et al. The MT domain of the proto-oncoprotein MLL binds to CpG-containing DNA and discriminates against methylation. Nucleic Acids Res 2002; 30:958–65.
Ayton PM, Chen EH, Cleary ML. Binding to nonmerhylated CpG DNA is essential for target recognition, transactivation and myeloid transformation by an MLL oncoprotein. Mol Cell Bio 2004; 24:10470–8.
Schultz DC, Friedman JR, Rauscher FJ 3rd. Targeting histone deacetylase complexes via KRAB-zinc finger proteins: the PHD and bromodomains of KAP-1 form a cooperative unit that recruits a novel isoform of the Mi-2alpha subunit of NuRD. Genes Dev 2001; 15:428–43.
Fair K, Anderson M, Bulanova E et al. Protein interactions of the MLL PHD fingers modulate MLL target gene regulation in human cells. Mol Cell Biol 2001; 21:3589–97.
Filetici P, PO, Ballario P. The bromodomain: a chromatin browser? Front Biosci 2001; 6:866–76.
Milne TA, Briggs SD, Brock HW et al. MLL targets SET domain methylrransferase activity to hox gene promoters. Mol Cell 2002; 10:1107–17.
Milne TA, Dou Y, Martin ME et al. MLL associates specificallywith a subset of transcriptionally active target genes. Proc Nat Acad Sci USA 2005; 102:14765–70.
Ernst P, Wang J, Huang M et al. MLL and CREB bind cooperatively to the nuclear coactivator CREB-binding protein. Mol Cell Biol 2001; 21:2249–58.
Petruk S, Sedkov Y, Smith S er al. Trithorax and dCBP acting in a complex to maintain expression of a homeotic gene. Science 2001; 294:1331–4.
DOll Y, Milne TA, Tackett AJ et al. Physical association and coordinate function of the H3 K4 rnethyltransferase MLL1 and the H4 K16 acetyltransferaseMOE Cell 2005; 121:873–85.
Yokoyama A, Wang Z, Wysocka J et al. Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate hox gene expression. Mol Cell Biol 2004; 24:5639–49.
Milne TA, Hughes CM, Lloyd R et al. Menin and MLL cooperatively regulate expression of cyelin-dependent kinase inhibitors. Proc Nat Acad Sci USA 2005; 102:749–54.
Wysocka J, Swigut T, Milne TA et al. WDR5 associates with histone H3 methylated at K4 and is essential for H3 K4 methylation and vertebrate development. Cell 2005; 121:859–72.
Agarwal SK, Lee Burns A, Sukhodolets KE et al. Molecular pathology of the MEN1 gene. Ann N Y Acad Sci 2004; 1014:189–98.
Agarwal SK. Guru SC, Heppner C et al. Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription. Cell 1999; 96:143–52.
Heppner C, Bilimoria KY, Agarwal SK et al. The tumor suppressor protein menin interacts with NF-kappaB proteins and inhibits NF-kappaB-mediated transactivation. Oncogene 2001; 20:4917–25.
Hughes CM, Rozenblatt-Rosen O, Milne TA et al. Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus. Mol Cell 2004; 13:587–97.
Yu BD, Hess JL, Horning SE et al. Altered hox expression and segmental identity in Mll-mutant mice. Nature 1995; 378:505–8.
Milne TA. Hughes CM. Lloyd R et al. Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. Proc Nat! Acad Sci USA 2005; 102:749–54.
Karnik SK, Hughes CM, Gu X et al. Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and pI8INK4c. Proc Nat Acad Sci USA 2005; 102:14659–64.
Scacheri PC, Davis S, Odorn DT et al. Genome-wide Analysis of menin binding provides insights into MEN1 tumorigenesis. PLoS Genetics 2006; 2:e51.
Schnepp RW, Chen YX, Wang H et al. Mutation of tumor suppressor gene menl acutely enhances proliferation of pancreatic islet cells. Cancer Res 2006; 66(11):5707–15.
Hess JL, Yu B D, Li B et al. Defects in yolk sac hematopoiesis in Mll-null embryos. Blood 1997; 90:1799–806.
Yagi H, Deguchi K, Aono A et al. Growth disturbance in fetal liver hematopoiesis of Mll-mutant mice. Blood 1998; 92:108–17.
Ernst P, Fisher JK, Avery W et al. Definitive hematopoiesis requires the mixed-lineage leukemia gene. Dev Cell 2004; 6:437–43.
Jude CD, Climer L, Xu D et al. Unique and independent roles for MLL in adult hematopoietic stem cells and progenitors. Cell Stem Cell 2007; 1:324–337.
McMahon KA, Hiew SYL, Hadjur S et al. MIl has a critical role in fetal and adult hematopoietic stem cell self-renewal. Cell Stem Cell 2007; 1:338–345.
Bertolino P, Radovanovic I, Casse H et al. Genetic ablation of the tumor suppressor menin causes lethality at mid-gestation with defects in multiple organs. Mech Dev 2003; 120:549–60.
Crabtree JS, Scacheri PC, Ward JM et al. Of mice and MEN1: Insulinomas in a conditional mouse knockout. Mol Cell Biol 2003; 23:6075–85.
Chen Y-X, Yan J, Keeshan K et al. The tumor suppressor menin regulates hematopoiesis and myeloid transformation by influencing hox gene expression. Proc Natl Acad Sci USA 2006; 103:1018–23.
Maillard I, Chen Y, Tubbs AT et al. Menin regulates the function of hematopoietic stem cells and lymphoid progenitors. Blood 2007; 110:379a.
Lawrence HJ, Helgason CD, Sauvageau G et al. Mice bearing a targeted interruption of the homeobox gene HOXA9 have defects in myeloid, erythroid and lymphoid hematopoiesis. Blood 1997; 89:1922–30.
Lawrence HJ, Christensen J, Fong S et al. Loss of expression of the hoxa-9 homeobox gene impairs the proliferation and repopulating ability of hematopoietic stem cells. Blood 2005; 106:3988–94.
Kroon E, Krosl J, Thorsteinsdottir U et al. Hoxa9 transforms primary bone marrow cells through specific collaboration with meis1a but not Pbx1b. EMBO J 1998; 17:3714–25.
Magli MC, Largman C, Lawrence HJ. Effects of HOX homeobox genes in blood cell differentiation. J Cell Physiol 1997; 173:168–77.
Lawrence HJ, Sauvageau G, Humphries RK et al. The role of HOX homeobox genes in normal and leukemic hematopoiesis. Stem Cells 1996; 14:281–91.
Pineault N, Helgason CD, Lawrence HJ et al. Differential expression of hox, meis1 and Pbx1 genes in primitive cells throughout murine hematopoietic ontogeny. Exp Hematol 2002; 30:49–57.
Armstrong SA, Staunton JE, Silverman LB et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet 2002; 30:41–7.
Rozovskaia T, Feinstein E, Mor O et al. Upregulation of Meis1 and HoxA9 in acute lymphocytic leukemias with the t(4∶11) abnormality. Oncogene 2001; 20:874–8.
Yeoh EJ, Ross ME, Shurtleff SA et al. Classification, subtype discovery and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell 2002; 1:133–43.
Nakamura T, Largaespada DA, Shaughnessy JD Jr et al. Cooperative activation of hoxa and Pbx1-related genes in murine myeloid leukaemias. Nat Genet 1996; 12:149–53.
Moskow JJ, Bullrich F, Huebner K et al. Meis1, a PBX1-related homeobox gene involved in myeloid leukemia in BXH-2 mice. Mol Cell Biol 1995; 15:5434–43.
Ayton PM, Cleary ML. Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins. Oncogene 2001; 20:5695–707.
Caslini C, Yang Z, El-Osea M et al. Interaction of MLL amino terminal sequences with menin is required for transformation. Cancer Res 2007; 67:7275–83.
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Maillard, I., Hess, J.L. (2009). The Role of Menin in Hematopoiesis. In: Balogh, K., Patocs, A. (eds) SuperMEN1. Advances in Experimental Medicine and Biology, vol 668. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-1664-8_5
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DOI: https://doi.org/10.1007/978-1-4419-1664-8_5
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