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

Jolanta Grembecka, Shihan He, Aibin Shi, Trupta Purohit, Andrew G. Muntean, Roderick J. Sorenson, Hollis D. Showalter, Marcelo J. Murai, Amalia M. Belcher, Thomas Hartley, Jay Hess, Tomasz Cierpicki

Research output: Contribution to journalArticle

188 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)277-284
Number of pages8
JournalNature Chemical Biology
Volume8
Issue number3
DOIs
StatePublished - Mar 2012
Externally publishedYes

Fingerprint

Myeloid-Lymphoid Leukemia Protein
Leukemia
Biphenotypic Acute Leukemia
Multiple Endocrine Neoplasia
Multiple Endocrine Neoplasia Type 1
Genes
Cell Differentiation
Down-Regulation
Apoptosis
Gene Expression

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Grembecka, J., He, S., Shi, A., Purohit, T., Muntean, A. G., Sorenson, R. J., ... Cierpicki, T. (2012). Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia. Nature Chemical Biology, 8(3), 277-284. https://doi.org/10.1038/nchembio.773

Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia. / 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; Cierpicki, Tomasz.

In: Nature Chemical Biology, Vol. 8, No. 3, 03.2012, p. 277-284.

Research output: Contribution to journalArticle

Grembecka, J, He, S, Shi, A, Purohit, T, Muntean, AG, Sorenson, RJ, Showalter, HD, Murai, MJ, Belcher, AM, Hartley, T, Hess, J & Cierpicki, T 2012, 'Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia', Nature Chemical Biology, vol. 8, no. 3, pp. 277-284. https://doi.org/10.1038/nchembio.773
Grembecka J, He S, Shi A, Purohit T, Muntean AG, Sorenson RJ et al. Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia. Nature Chemical Biology. 2012 Mar;8(3):277-284. https://doi.org/10.1038/nchembio.773
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 ; Cierpicki, Tomasz. / Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia. In: Nature Chemical Biology. 2012 ; Vol. 8, No. 3. pp. 277-284.
@article{f2dd1be3e72940579ad94e6a7446dc65,
title = "Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia",
abstract = "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.",
author = "Jolanta Grembecka and Shihan He and Aibin Shi and Trupta Purohit and Muntean, {Andrew G.} and Sorenson, {Roderick J.} and Showalter, {Hollis D.} and Murai, {Marcelo J.} and Belcher, {Amalia M.} and Thomas Hartley and Jay Hess and Tomasz Cierpicki",
year = "2012",
month = "3",
doi = "10.1038/nchembio.773",
language = "English (US)",
volume = "8",
pages = "277--284",
journal = "Nature Chemical Biology",
issn = "1552-4450",
publisher = "Nature Publishing Group",
number = "3",

}

TY - JOUR

T1 - Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia

AU - Grembecka, Jolanta

AU - He, Shihan

AU - Shi, Aibin

AU - Purohit, Trupta

AU - Muntean, Andrew G.

AU - Sorenson, Roderick J.

AU - Showalter, Hollis D.

AU - Murai, Marcelo J.

AU - Belcher, Amalia M.

AU - Hartley, Thomas

AU - Hess, Jay

AU - Cierpicki, Tomasz

PY - 2012/3

Y1 - 2012/3

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84857195696&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84857195696&partnerID=8YFLogxK

U2 - 10.1038/nchembio.773

DO - 10.1038/nchembio.773

M3 - Article

C2 - 22286128

AN - SCOPUS:84857195696

VL - 8

SP - 277

EP - 284

JO - Nature Chemical Biology

JF - Nature Chemical Biology

SN - 1552-4450

IS - 3

ER -