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A novel tubulin binding molecule drives differentiation of acute myeloid leukaemia cells

ABSTRACT: Acute Myeloid Leukaemia (AML) continues to have a poor prognosis, especially in the elderly. One reason for this is that many treatment regimens are not well tolerated by elderly patients. Much current focus is on the development of therapies that can target specific vulnerabilities of AML while having fewer toxic side effects. However, despite much recent progress in developing better drugs, many patients with AML still die within a year of diagnosis, partly due to the fact that it is difficult to identify therapeutic targets that are effective across multiple AML subtypes. One common factor across AML subtypes is the presence of a block in differentiation. Thus screening for compounds that can overcome this block in genetically diverse AML models should allow for the identification of agents that are not dependent on a specific mutation for their efficacy. Here, we used a phenotypic screen to identify novel compounds that stimulate differentiation in several AML cell lines. Lead compounds were shown to decrease tumour burden and to increase survival in vivo. Using multiple complementary target deconvolution approaches, these compounds were revealed to be anti-mitotic tubulin disruptors that cause differentiation by inducing a G2-M mitotic arrest. Together, these results reveal a novel function for tubulin disruptors in causing differentiation of AML cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE178787 | GEO | 2022/06/01

REPOSITORIES: GEO

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A novel tubulin binding molecule drives differentiation of acute myeloid leukaemia cells

Project description:Here we perform a phenotypic screen and identified novel compounds that can promote differentiation in several AML cell lines. Lead compounds are able to decrease tumour burden and increase survival in vivo. Using multiple complementary target deconvolution approaches (including chemoproteomics), these compounds were revealed to be anti-mitotic tubulin disruptors that cause differentiation by inducing a G2-M mitotic arrest. Together, these results reveal a novel function for tubulin disruptors in causing differentiation of AML cells.

2021-11-02 | PXD022038 | Pride

Thalicthuberine: A Novel Mitotic Inhibitor in Prostate Cancer Cells

Project description:Bioassay-guided fractionation of a cytotoxic extract derived from the Australian endemic plant Hernandia albiflora (twigs) resulted in the isolation of the two known compounds: deoxypodophyllotoxin and thalicthuberine. Both compounds were tested for their inhibition of LNCaP cell viability. Thalicthuberine (TH, IC50=2.0 µM) was selected for mechanism of action studies. Ongoing investigations have shown that TH induced a strong accumulation of LNCaP cells in mitosis, severe mitotic spindle defects and asymmetric cell divisions, ultimately leading to mitotic catastrophe accompanied by cell death through apoptosis. However, unlike microtubule-targeting drugs (vinblastine, paclitaxel and nocodazole), TH did not affect tubulin polymerization in a cell-free system, while it reduced cellular microtubule polymer mass, suggesting that TH indirectly targets microtubule dynamics through inhibition of critical regulators or tubulin-associated proteins. Based on phenotypic comparisons, we excluded the mitotic regulators Aurora kinase A and Polo-like kinase 1 as potential targets of TH. TH did not directly interact with DNA (cell-free assay) or induce DNA damage in cells. Further experiments will attempt to address the molecular target(s) and inhibition mechanism of TH. This is the first report of a mechanism of action study for this natural product. Based on these results, TH has great promise for further development into a potent non-tubulin-targeting mitotic inhibitor.

2016-06-17 | GSE83459 | GEO

Transcription Factor MEF2D is Required for the Maintenance of MLL-rearranged Acute Myeloid Leukemia [ATAC-Seq]

Project description:Acute myeloid leukemia (AML) with MLL-rearrangement (MLL-r) comprises approximately 10% of all AML cases and portends poor outcomes. Much remains to be uncovered on how MLL-r AML drives leukemia development while preventing cells from normal myeloid differentiation. Here, we identified that transcription factor MEF2D is a highly expressed gene with a super-enhancer MLL-r AML. Knockout of MEF2D profoundly impaired leukemia growth, induced myeloid differentiation, and delayed oncogenic progression in vivo. Mechanistically, MEF2D loss led to robust activation of a CEBPE-centered myeloid differentiation program in AML cells. Chromatin profiling revealed that MEF2D binds to and suppresses the chromatin accessibility of CEBPE cis-regulatory regions. In human acute leukemia patient samples, MEF2D expression showed a strong negative correlation with the expression of CEBPE. Depletion of CEBPE partially rescued the cell growth defect and myeloid cell differentiation induced by the loss of MEF2D. Lastly, we show that MEF2D is positively regulated by HOXA9, and downregulation of MEF2D is an important mechanism for DOT1L inhibitor-induced anti-leukemia effects in MLL-r AML. Collectively, our findings suggest that MEF2D plays a critical role in human MLL-r AML and uncover the MEF2D-CEBPE axis as a crucial transcriptional mechanism regulating leukemia cell self-renewal and differentiation block in MLL-r AML.

2021-10-02 | GSE165979 | GEO

Transcription Factor MEF2D is Required for the Maintenance of MLL-rearranged Acute Myeloid Leukemia [RNA-Seq]

2021-10-03 | GSE165981 | GEO

Transcription Factor MEF2D is Required for the Maintenance of MLL-rearranged Acute Myeloid Leukemia [ChIP-Seq]

2021-10-02 | GSE165980 | GEO

Increased expression of RUNX3 inhibits normal human myeloid development

Project description:In this study, RUNX3 expression was analyzed in normal and malignant haematopoiesis and the impact of its dysregulation on myelopoiesis was further determined. We found that RUNX3 was highly expressed in haematopoietic progenitors, with its levels reducing towards granulocytic differentiation. In AML, RUNX3 was overexpressed across all different subtypes except in core binding factor AML where it was downregulated. RUNX3 overexpression in human haematopoietic stem and progenitor cells (HSPC) inhibited myeloid development, particularly granulopoiesis. Further RNA-sequencing studies showed that RUNX3 overexpression downregulates key hematopoietic genes, while upregulating certain lymphoid genes. Overall, this study suggests that increased RUNX3 expression could contribute to the myeloid block characteristic of AML by possibly driving a competing transcriptional program favoring the lymphoid fate.

2022-04-13 | GSE181059 | GEO

Novel IDH1 Mutant Inhibitors for Treatment of Acute Myeloid Leukemia (expression)

Project description:Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are driver mutations in acute myeloid leukemia (AML) and other cancers. We report the development of new allosteric inhibitors of mutant IDH1. Crystallographic and biochemical results demonstrated that compounds of this chemical series bind to an allosteric site and lock the enzyme in a catalytically inactive conformation, thereby enabling inhibition of different clinically relevant IDH1 mutants. Treatment of IDH1 mutant primary AML cells uniformly led to a decrease in intracellular 2-HG, abrogation of the myeloid differentiation block and induction of granulocytic differentiation at the level of leukemic blasts and more immature stem-like cells, in vitro and in vivo. Molecularly, treatment with the inhibitors led to a reversal of the DNA cytosine hypermethylation patterns caused by mutant IDH1 in AML patients’ cells. Our study provides proof-of-concept for the molecular and biological activity of novel allosteric inhibitors for targeting different mutant forms of IDH1 in leukemia. To obtain insight into the molecular mechanism for the induction of granulocytic differentiation and cell death following inhibition of IDH1 mutant protein in primary AML cells, we performed gene expression microarrays following treatment with either GSK321 IDH1 inhibitor or Controls (DMSO or GSK990 inactive inhibitor). Primary IDH1 mutant acute myeloid leukemia (AML) mononuclear (MNC) cells were treated in suspension cultures in differentiating media for 6 days with 3 microM GSK990 or GSK321 and an equal volume of DMSO. Followed by microarray analysis after RNA extraction.

2015-09-21 | E-GEOD-72152 | biostudies-arrayexpress

Expression data of AML cells treated with out without H4

Project description:Safer and more efficient therapy for patients with acute myeloid leukemia (AML) is needed and differentiation therapy is an appealing option to eradicate leukemic stem cells blocked in differentiation. With the aim of identifying new AML differentiating agents/molecules, we screened 528 natural compounds on primary AML samples. Compounds that upregulated the expression of the myeloid differentiation markers CD11b/CD15 were considered as positive hits. Among those, a macrocyclic diterpenecalled H4 upregulated expression of CD11b (DMSO 22±5%, H4 66±8% SEM), which was accompanied with a clear decrease in nuclear-cytoplasmic ratio, on patient cells with AML subtype M5. To identify the mechansim AML cells were treated with H4 for 16 hrs followed by gene expression analysis.

2019-07-01 | GSE126439 | GEO

Novel IDH1 Mutant Inhibitors for Treatment of Acute Myeloid Leukemia (ERRBS)

Project description:Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are driver mutations in acute myeloid leukemia (AML) and other cancers. We report the development of new allosteric inhibitors of mutant IDH1. Crystallographic and biochemical results demonstrated that compounds of this chemical series bind to an allosteric site and lock the enzyme in a catalytically inactive conformation, thereby enabling inhibition of different clinically relevant IDH1 mutants. Treatment of IDH1 mutant primary AML cells uniformly led to a decrease in intracellular 2-HG, abrogation of the myeloid differentiation block and induction of granulocytic differentiation at the level of leukemic blasts and more immature stem-like cells, in vitro and in vivo. Molecularly, treatment with the inhibitors led to a reversal of the DNA cytosine hypermethylation patterns caused by mutant IDH1 in AML patients’ cells. Our study provides proof-of-concept for the molecular and biological activity of novel allosteric inhibitors for targeting different mutant forms of IDH1 in leukemia. To obtain insight into the molecular mechanism of the novel IDH1 mutant allosteric inhibitor, primary AML cells were treated with either GSK321 IDH1 active inhibitor or Controls (DMSO or GSK990 inactive inhibitor) followed by DNA extraction for ERRBS analysis. Primary IDH1 mutant acute myeloid leukemia (AML) mononuclear (MNC) cells were treated in suspension cultures in differentiating media for 6 days with 3 microM GSK990 or GSK321 and an equal volume of DMSO, Followed ERRBS analysis after DNA extraction.

2015-09-21 | E-GEOD-72247 | biostudies-arrayexpress

caArray_golub-00392: Gefitinib (Iressa) induces myeloid differentiation of acute myeloid leukemia

Project description:Cure rates for patients with acute myeloid leukemia (AML) remain low despite ever-increasing dose intensity of cytotoxic therapy. In an effort to identify novel approaches to AML therapy, we recently reported a new method of chemical screening based on the modulation of a gene expression signature of interest. We applied this approach to the discovery of AML-differentiation-promoting compounds. Among the compounds inducing neutrophilic differentiation was DAPH1 (4,5-dianilinophthalimide), previously reported to inhibit epidermal growth factor receptor (EGFR) kinase activity. Here we report that the Food and Drug Administration (FDA)-approved EGFR inhibitor gefitinib similarly promotes the differentiation of AML cell lines and primary patient-derived AML blasts in vitro. Gefitinib induced differentiation based on morphologic assessment, nitro-blue tetrazolium reduction, cell-surface markers, genome-wide patterns of gene expression, and inhibition of proliferation at clinically achievable doses. Importantly, EGFR expression was not detected in AML cells, indicating that gefitinib functions through a previously unrecognized EGFR-independent mechanism. These studies indicate that clinical trials testing the efficacy of gefitinib in patients with AML are warranted. golub-00392 Assay Type: Gene Expression Provider: Affymetrix Array Designs: HG-U133A, HG-U133A_2 Organism: Homo sapiens (ncbitax) Material Types: cell, total_RNA, synthetic_RNA, organism_part, whole_organism*Cell Types: Disease States: Acute Myeloid Leukemia, Normal, Acute Myeloid Leukemia

2015-05-16 | E-GEOD-68954 | biostudies-arrayexpress

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