The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis.
The Mixed-Lineage Leukemia (MLL) protein is a histone methyltransferase that is mutated in clinically and biologically distinctive subsets of acute leukemia. MLL normally associates with a cohort of highly conserved cofactors to form a macromolecular complex that includes menin, a product of the MEN1 tumor suppressor gene, which is mutated in heritable and sporadic endocrine tumors. We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis. Furthermore, menin is essential for maintenance of MLL-associated but not other oncogene induced myeloid transformation. Acute genetic ablation of menin reverses aberrant Hox gene expression mediated by MLL-menin promoter-associated complexes, and specifically abrogates the differentiation arrest and oncogenic properties of MLL-transformed leukemic blasts. These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity, validate a potential target for molecular therapy, and suggest central roles for menin in altered epigenetic functions underlying the pathogenesis of hematopoietic cancers.
Yokoyama
Akihiko
A
Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.
Somervaille
Tim C P
TC
Smith
Kevin S
KS
Rozenblatt-Rosen
Orit
O
Meyerson
Matthew
M
Cleary
Michael L
ML
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D047369:Chromatin Immunoprecipitation; D016384:Consensus Sequence; D017124:Conserved Sequence; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007951:Leukemia, Myeloid / Q000209:etiology*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008969:Molecular Sequence Data; D023461:Myeloid Progenitor Cells; D051788:Myeloid-Lymphoid Leukemia Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D018398:Homeodomain Proteins; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins; D051788:Myeloid-Lymphoid Leukemia Protein