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

Grembecka, Jolanta; He, Shujiao; 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

doi:10.1038/nchembio.773

Cited by 358 publications

(397 citation statements)

References 43 publications

Supporting

Mentioning

392

Contrasting

Order By: Relevance

“…MI-2 induces cell growth arrest, terminal differentiation, and blocks transformation by MLL fusions. MI-2 treatment may downregulate the expression of MLL fusion target genes in particular; MI-2 treatment reduces Menin-MLL-AF9 occupancy on the Hoxa9 locus and impairs Hoxa9 expression [61]. These results suggest that Menin-MLL inhibitors are also feasible targets and are as capable of reversing the leukemogenic activity of MLL fusion proteins as the epigenetic inhibitors (Fig.…”

Section: Recent Trials Of Epigenetic Therapy Targeting Mll Leukemiamentioning

confidence: 58%

Disordered epigenetic regulation in MLL-related leukemia

et al. 2012

View full text Add to dashboard Cite

Leukemias bearing rearrangements of chromosome 11q23 are of particular interest due to their unique clinical and biological characteristics. 11q23 abnormalities occur in up to 70 % of infant leukemias, and about 10 % of adult acute myelogenous leukemias (AML). Two major rearrangements of the MLL gene are found in MLL-related leukemia. The most common of these is balanced translocations in which the N-terminal portion of MLL is fused to the C-terminus of the translocation partner. To date, nearly 100 different chromosome bands have been described in rearrangements involving MLL, and more than 70 known fusion partners of MLL have been cloned and characterized at the molecular level. Another major aberration of the MLL gene creates a repeat within the N-terminal MLL resulting in an internal partial tandem duplication (PTD). As a consequence, an extra amino-terminus is added in-frame to full-length MLL, resulting in leukemogenic MLL-PTD. MLL-PTD occurs predominantly in myeloid dysplasia syndromes, secondary AML (s-AML), and de novo AML. The presence of an MLL rearrangement generally confers a poor prognosis. MLL fusions and MLL-PTD are transcriptional regulators that take control of targets normally controlled by MLL, with the clustered HOX homeobox genes as prominent examples. Several epigenetic regulators that modify DNA or histones have been implicated in MLL fusion driven leukemogenesis, including DNA methylation, histone acetylation, and histone methylation. Recently, the histone methyltransferase DOT1L, the bromodomain and extra-terminal (BET) family member BRD4, and the MLL-interacting protein Menin have emerged as important mediators of MLL fusion-mediated leukemic transformation. The clinical development of targeted inhibitors of these epigenetic regulators has heralded promise for the treatment of MLL fusion leukemia. Although the biological function and molecular mechanism for MLL-PTD remains largely unknown, based on the primary protein structure of MLL-PTD and the knowledge gained so far from MLL fusions, newly developed inhibitors of epigenetic regulators could potentially also prove effective in the treatment of MLL-PTD related leukemias.

show abstract

Section: Recent Trials Of Epigenetic Therapy Targeting Mll Leukemiamentioning

confidence: 58%

Disordered epigenetic regulation in MLL-related leukemia

et al. 2012

View full text Add to dashboard Cite

show abstract

“…MLL-rearranged mixed lineage leukaemia is driven by chromosomal translocations that result in an oncogenic fusion protein comprising the amino terminal region of MLL and the carboxy terminus of one of B70 translocation partners 14 , and pharmacological targeting of MLL translocation complexes was recently shown to reverse oncogenic activity of MLL fusion proteins in leukemia 15 . A subset of MLL fusion partners, including AF4, AF9 and AF10, aberrantly recruit DOT1L to select genomic loci leading to increased H3K79 methylation and transcriptional activation of genes essential for leukemogenesis 16 .…”

mentioning

confidence: 99%

Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

et al. 2012

View full text Add to dashboard Cite

Selective inhibition of protein methyltransferases is a promising new approach to drug discovery. An attractive strategy towards this goal is the development of compounds that selectively inhibit binding of the cofactor, S-adenosylmethionine, within specific protein methyltransferases. Here we report the three-dimensional structure of the protein methyltransferase DOT1L bound to EPZ004777, the first S-adenosylmethionine-competitive inhibitor of a protein methyltransferase with in vivo efficacy. This structure and those of four new analogues reveal remodelling of the catalytic site. EPZ004777 and a brominated analogue, SGC0946, inhibit DOT1L in vitro and selectively kill mixed lineage leukaemia cells, in which DOT1L is aberrantly localized via interaction with an oncogenic MLL fusion protein. These data provide important new insight into mechanisms of cell-active S-adenosylmethioninecompetitive protein methyltransferase inhibitors, and establish a foundation for the further development of drug-like inhibitors of DOT1L for cancer therapy.

show abstract

“…The MTT viability assay was carried out using a recently published protocol. 20 For growth curves, 3 ϫ 10 5 /mL cells were plated (1 mL/well) and treated with compounds or 0.25% DMSO. Media were changed every 48 hours with viable cell concentration restored to 3 ϫ 10 5 cells/mL and compound resupplied.…”

Section: Coimmunoprecipitation Experimentsmentioning

confidence: 99%

“…20 One of these compounds, MI-2 (IC 50 ϭ 446 nM), showed pronounced effects in MLL leukemia cells, representing a very promising lead compound for the development of new antileukemic agents. 20 However, lack of structural data for the MI-2 interaction with menin impeded the development of more potent inhibitors of the menin-MLL interaction. To overcome this limitation, we determined the 1.56 Å resolution structure of MI-2 bound to menin (Figure 2A-B, supplemental Figure 11, and supplemental Table 1), which represents the first determination of the crystal structure of menin in complex with a small-molecule inhibitor.…”

mentioning

confidence: 99%

“…The structure also rationalizes why substitution of the n-propyl by bulky hydrophobic groups did not improve binding affinity. 20 To develop more potent compounds, we used structural information and designed several modifications of the R1 substituent on the thienopyrimidine ring ( Figure 3A). First, we introduced oxygen, which could form a hydrogen bond with the side chain hydroxyl of Ser155.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia

Shi

Murai

et al. 2012

Blood

Self Cite

167

260

View full text Add to dashboard Cite

Menin functions as a critical oncogenic cofactor of mixed lineage leukemia (MLL) fusion proteins in the development of acute leukemias, and inhibition of the menin interaction with MLL fusion proteins represents a very promising strategy to reverse their oncogenic activity. MLL interacts with menin in a bivalent mode involving 2 N-terminal fragments of MLL. In the present study, we reveal the first high-resolution crystal structure of human menin in complex with a smallmolecule inhibitor of the menin-MLL interaction, MI-2. The structure shows that the compound binds to the MLL pocket in menin and mimics the key interactions of MLL with menin. Based on the menin-MI-2 structure, we developed MI-2-2, a compound that binds to menin with low nanomolar affinity (K d ‫؍‬ IntroductionTranslocations of the MLL (mixed lineage leukemia) gene frequently occur in aggressive human acute myeloid and lymphoid leukemias in both children and adults. 1 Fusion of MLL with 1 of more than 60 different genes results in chimeric MLL fusion proteins that enhance proliferation and block hematopoietic differentiation, ultimately leading to acute leukemia. 2 Patients with leukemias harboring MLL translocations have very unfavorable prognoses and respond poorly to currently available treatments. 2,3 The relapse risk is very high using conventional chemotherapy and stem cell transplantation, 2 leading to an overall 5-year survival rate of only approximately 35%. 4 All MLL fusion proteins preserve an N-terminal MLL fragment approximately 1400 amino acids in length fused in-frame with the C-terminus of the fusion partner. 3,[5][6][7] Two regions in this fragment of MLL have been shown to be indispensable for leukemogenic transformation: the N-terminal region, which binds to menin 8 and to lens epithelium-derived growth factor (LEDGF), 9 and the conserved region encompassing the CXXC domain, which mediates binding to nonmethylated CpG DNA [10][11][12] and interacts with the polymerase associated factor complex (PAFc). 13,14 Targeting these interactions provides new opportunities for the development of new therapeutic agents for the MLL leukemias. 15 Menin is a tumor-suppressor protein encoded by the MEN1 (multiple endocrine neoplasia 1) gene. 16 Mutations of MEN1 are associated with tumors of the parathyroid glands, pancreatic islet cells, and anterior pituitary gland. 17 Menin is also a highly specific binding partner for MLL and MLL fusion proteins and is required to regulate the expression of MLL target genes, including HOXA9 and MEIS1. 8 Loss of the ability to bind menin abolishes the oncogenic potential of MLL fusion proteins both in vitro and in vivo. 8 Disruption of the interaction between menin and MLL fusion proteins using genetic methods blocks the development of acute leukemia in mice, 8 indicating that menin functions as a critical oncogenic cofactor of MLL fusion proteins and is required for their leukemogenic activity. The menin-MLL interaction represents an attractive therapeutic target for the development of novel drugs for acut...

show abstract

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

Cited by 358 publications

References 43 publications

Disordered epigenetic regulation in MLL-related leukemia

Disordered epigenetic regulation in MLL-related leukemia

Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia

Contact Info

Product

Resources

About