Inhibition of Myb-dependent gene expression by the sesquiterpene lactone mexicanin-I

Bujnicki, Tuyen; Wilczek, Carola; Schomburg, Caroline; Feldmann, Friedericke; Schlenke, Peter; Müller‐Tidow, Carsten; Schmidt, Thomas J.; Kh, Klempnauer

doi:10.1038/leu.2011.275

Cited by 38 publications

(50 citation statements)

References 49 publications

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“…We have recently developed a reporter cell line that allows monitoring Myb activity by the fluorescence of the cells (5,44). This cell system is based on the chicken HD11 cell line that was stably transfected with a Mybresponsive GFP reporter gene driven by the promoter and enhancer of the Myb-inducible chicken mim-1 gene (22) and a doxycycline-inducible expression system for c-Myb (Fig.…”

Section: Naphthol As-e Phosphate Inhibits Myb Activity In Vivo and Inmentioning

confidence: 99%

“…Apoptosis was analyzed with the Trevigen TACS annexin V kit (Gentaur GmbH). Real-time PCR was performed as described previously (5). The data were analyzed by subtracting the C T values for c-myc (or Ada) mRNA from those for b-actin mRNA, thereby normalizing the amount of c-myc (or Ada) mRNA to that of b-actin mRNA.…”

Section: In Vivo Assaysmentioning

confidence: 99%

“…Northern blotting of mim-1 and ribosomal protein S17 mRNAs was performed as described previously (5). Differentiation assays were performed by culturing HL60, U937, or NB4 cells for 2 days in RPMI-1640 medium containing napthol AS-E phosphate.…”

Section: In Vivo Assaysmentioning

confidence: 99%

“…Recently, c-Myb has attracted attention as a potential drug target for the treatment of leukemia and other tumors (5,6). Myb was initially discovered as the retroviral oncogene (v-myb) of avian myeloblastosis virus (7).…”

Section: Introductionmentioning

confidence: 99%

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Naphthol AS-E Phosphate Inhibits the Activity of the Transcription Factor Myb by Blocking the Interaction with the KIX Domain of the Coactivator p300

Uttarkar

Dukare

Bopp

et al. 2015

Molecular Cancer Therapeutics

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The transcription factor c-Myb is highly expressed in hematopoietic progenitor cells and controls the transcription of genes important for lineage determination, cell proliferation, and differentiation. Deregulation of c-Myb has been implicated in the development of leukemia and certain other types of human cancer. c-Myb activity is highly dependent on the interaction of the c-Myb with the KIX domain of the coactivator p300, making the disruption of this interaction a reasonable strategy for the development of Myb inhibitors. Here, we have used bacterial Autodisplay to develop an in vitro binding assay that mimics the interaction of Myb and the KIX domain of p300. We have used this binding assay to investigate the potential of Naphthol AS-E phosphate, a compound known to bind to the KIX domain, to disrupt the interaction between Myb and p300. Our data show that Naphthol AS-E phosphate interferes with the Myb-KIX interaction in vitro and inhibits Myb activity in vivo. By using several human leukemia cell lines, we demonstrate that Naphthol AS-E phosphate suppresses the expression of Myb target genes and induces myeloid differentiation and apoptosis. Our work identifies Naphthol AS-E phosphate as the first low molecular weight compound that inhibits Myb activity by disrupting its interaction with p300, and suggests that inhibition of the Myb-KIX interaction might be a useful strategy for the treatment of leukemia and other tumors caused by deregulated c-Myb.

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Section: Naphthol As-e Phosphate Inhibits Myb Activity In Vivo and Inmentioning

confidence: 99%

Section: In Vivo Assaysmentioning

confidence: 99%

Section: In Vivo Assaysmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Naphthol AS-E Phosphate Inhibits the Activity of the Transcription Factor Myb by Blocking the Interaction with the KIX Domain of the Coactivator p300

Uttarkar

Dukare

Bopp

et al. 2015

Molecular Cancer Therapeutics

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“…During this work, we discovered that the triterpenoid Celastrol ( Figure 1C) inhibits Myb activity strongly (50% effective concentration [EC 50 ] ;0.85 mM) and slightly more potently than Mexicanin-I (EC 50 ;1.8 mM), which was previously shown to inhibit Myb activity. 38,39 Cell viability assays showed that the inhibitory effect of Celastrol was not caused by a general toxic effect. Celastrol also inhibited the activation of the endogenous mim-1 gene ( Figure 1E), demonstrating that Celastrol inhibits Myb activity also in the context of an endogenous Myb target gene.…”

mentioning

confidence: 99%

Targeting acute myeloid leukemia with a small molecule inhibitor of the Myb/p300 interaction

Uttarkar

Dassé

Coulibaly³

et al. 2016

Blood

129

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Key Points• Inhibition of Myb activity by a small molecule blocks proliferation of AML cells and prolongs survival of mice in an in vivo AML model.The transcription factor Myb plays a key role in the hematopoietic system and has been implicated in the development of leukemia and other human cancers. Inhibition of Myb is therefore emerging as a potential therapeutic strategy for these diseases. However, because of a lack of suitable inhibitors, the feasibility of therapeutic approaches based on Myb inhibition has not been explored. We have identified the triterpenoid Celastrol as a potent low-molecular-weight inhibitor of the interaction of Myb with its cooperation partner p300. We demonstrate that Celastrol suppresses the proliferative potential of acute myeloid leukemia (AML) cells while not affecting normal hematopoietic progenitor cells. Furthermore, Celastrol prolongs the survival of mice in a model of an aggressive AML. Overall, our work demonstrates the therapeutic potential of a small molecule inhibitor of the Myb/p300 interaction for the treatment of AML and provides a starting point for the further development of Myb-inhibitory compounds for the treatment of leukemia and, possibly, other tumors driven by deregulated Myb. (Blood. 2016;127(9):1173-1182 Introduction Myb, the protein encoded by the MYB proto-oncogene, is now recognized as an attractive therapeutic target for the treatment of leukemia and potentially for other human tumors.1 Myb was originally discovered as the cellular progenitor of the transforming v-Myb transduced by avian myeloblastosis virus. 2,3 Myb is expressed in the hematopoietic progenitor cells, where it acts as a transcription factor to control genes important for lineage determination, cell proliferation, and differentiation. 4,5 The analysis of Myb null and conditional knockout mice and of mice bearing hypomorphic Myb alleles has demonstrated that Myb is essential for most hematopoietic lineages. [6][7][8][9][10][11] Myb is also expressed in several nonhematopoietic tissues, 12 such as the colonic crypts, where it controls the proliferation and differentiation of the intestinal stem cells. 13 Recent work has shown that deregulated Myb plays critical roles in leukemias and other types of cancer. Recurrent translocations and duplications of the Myb locus occur in acute lymphoblastic leukemia of young children. [14][15][16] In addition, genomic rearrangements of Myb have been reported in acute myelomonocytic and basophilic leukemia. [17][18][19] Although such rearrangements are relatively rare, they indicate that aberrant Myb expression contributes to the development of leukemia. Importantly, it has now been realized that Myb also plays essential roles in leukemias caused by genetic lesions of other genes, such as leukemias driven by human acute myeloid leukemia (AML) oncogenes. [20][21][22][23][24][25][26] High expression of Myb is a common characteristic of these leukemias and is essential for maintenance of the leukemic cells. This was initially observed in studies with Myb ant...

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MYB as a Critical Transcription Factor and Potential Therapeutic Target in AML

Clarke,

Gabrielsen,

Frampton

2024

Transcription Factors in Blood Cell Development

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Inhibition of Myb-dependent gene expression by the sesquiterpene lactone mexicanin-I

Cited by 38 publications

References 49 publications

Naphthol AS-E Phosphate Inhibits the Activity of the Transcription Factor Myb by Blocking the Interaction with the KIX Domain of the Coactivator p300

Naphthol AS-E Phosphate Inhibits the Activity of the Transcription Factor Myb by Blocking the Interaction with the KIX Domain of the Coactivator p300

Targeting acute myeloid leukemia with a small molecule inhibitor of the Myb/p300 interaction

MYB as a Critical Transcription Factor and Potential Therapeutic Target in AML

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