Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia

MLL fusion genes often encode leukemogenic proteins that depend on interaction with menin, a component of the MLL SET1-like histone methyltransferase complex. MI-2 and MI-3 are the first small molecules that can block menin–MLL fusion protein interaction and their oncogenic effects in cells. Translo...

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Veröffentlicht in:Nature chemical biology 2012-01, Vol.8 (3), p.277-284
Hauptverfasser: Grembecka, Jolanta, He, Shihan, Shi, Aibin, Purohit, Trupta, Muntean, Andrew G, Sorenson, Roderick J, Showalter, Hollis D, Murai, Marcelo J, Belcher, Amalia M, Hartley, Thomas, Hess, Jay L, Cierpicki, Tomasz
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container_issue 3
container_start_page 277
container_title Nature chemical biology
container_volume 8
creator Grembecka, Jolanta
He, Shihan
Shi, Aibin
Purohit, Trupta
Muntean, Andrew G
Sorenson, Roderick J
Showalter, Hollis D
Murai, Marcelo J
Belcher, Amalia M
Hartley, Thomas
Hess, Jay L
Cierpicki, Tomasz
description MLL fusion genes often encode leukemogenic proteins that depend on interaction with menin, a component of the MLL SET1-like histone methyltransferase complex. MI-2 and MI-3 are the first small molecules that can block menin–MLL fusion protein interaction and their oncogenic effects in cells. Translocations involving the mixed lineage leukemia ( MLL ) gene result in human acute leukemias with very poor prognosis. The leukemogenic activity of MLL fusion proteins is critically dependent on their direct interaction with menin, a product of the multiple endocrine neoplasia ( MEN1 ) gene. Here we present what are to our knowledge the first small-molecule inhibitors of the menin–MLL fusion protein interaction that specifically bind menin with nanomolar affinities. These compounds effectively reverse MLL fusion protein–mediated leukemic transformation by downregulating the expression of target genes required for MLL fusion protein oncogenic activity. They also selectively block proliferation and induce both apoptosis and differentiation of leukemia cells harboring MLL translocations. Identification of these compounds provides a new tool for better understanding MLL-mediated leukemogenesis and represents a new approach for studying the role of menin as an oncogenic cofactor of MLL fusion proteins. Our findings also highlight a new therapeutic strategy for aggressive leukemias with MLL rearrangements.
doi_str_mv 10.1038/nchembio.773
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subjects 631/92/556
631/92/613
631/92/96
692/699/67/1990/283
Animals
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Apoptosis
Apoptosis - drug effects
Biochemical Engineering
Biochemistry
Bioorganic Chemistry
Cell Biology
Cell Differentiation - drug effects
Cell proliferation
Cell Proliferation - drug effects
Cells, Cultured
Chemistry
Chemistry and Materials Science
Chemistry/Food Science
Cofactors
Differentiation
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Fusion protein
Gene expression
HEK293 Cells
Histone-Lysine N-Methyltransferase
Humans
Inhibitors
Leukemia
Leukemia - drug therapy
Leukemia - genetics
Leukemia - metabolism
Leukemia - pathology
Leukemogenesis
MEN1 protein
Mice
MLL protein
Molecular biology
multiple endocrine neoplasia
Mutation
Myeloid-Lymphoid Leukemia Protein - antagonists & inhibitors
Myeloid-Lymphoid Leukemia Protein - genetics
Myeloid-Lymphoid Leukemia Protein - metabolism
Oncology
Prognosis
Proteins
Proto-Oncogene Proteins - antagonists & inhibitors
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
Structure-Activity Relationship
Transformation
Translocation
title Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia
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