The gene signature in CCAAT-enhancer-binding protein   dysfunctional acute myeloid leukemia predicts responsiveness to histone deacetylase inhibitors

Liss, Adam L.; Ooi, Chia Huey; Zjablovskaja, Polina; Benoukraf, Touati; Radomska, Hanna S.; Chen, Ju; Wu, Mengchu; Balastik, Martin; Delwel, Ruud; Brdička, Tomáš; Tan, Patrick; Tenen, Daniel G.; Alberich-Jordà, Meritxell

doi:10.3324/haematol.2013.093278

Cited by 14 publications

(15 citation statements)

References 46 publications

(40 reference statements)

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“…CMAP has previously been used for drug repurposing 21,22,23 . By using input signatures specific to leukaemia cells or TFs as the input to CMAP, other studies have identified drugs which eliminate leukaemia cells, induce their differentiation or the loss of self-renewal 24,25,26,27 . Here we extend this approach at the network level, using Mogrify-identified TFs and their networks as the input signature for CMAP, to identify differentiation-inducing drugs.…”

Section: Introductionmentioning

confidence: 99%

Identification of drugs for leukaemia differentiation therapy by network pharmacology

et al. 2019

Preprint

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Acute leukaemias differ from their normal haematopoietic counterparts in their inability to differentiate. This phenomenon is thought to be the result of aberrant cellular reprogramming involving transcription factors (TFs). Here we leveraged on Mogrify, a network-based algorithm, to identify TFs and their gene regulatory networks that drive differentiation of the acute promyelocytic leukaemia (APL) cell line NB4 in response to ATRA (all-trans retinoic acid). We further integrated the detected TF regulatory networks with the Connectivity Map (CMAP) repository and recovered small molecule drugs which induce similar transcriptional changes. Our method outperformed standard approaches, retrieving ATRA as the top hit. Of the other drug hits, dimaprit and mebendazole enhanced ATRA-mediated differentiation in both parental NB4 and ATRA-resistant NB4-MR2 cells. Thus, we provide proof-of-principle of our network-based computational platform for drug discovery and repositioning in leukaemia differentiation therapy, which can be extended to other dysregulated disease states.

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Section: Introductionmentioning

confidence: 99%

Identification of drugs for leukaemia differentiation therapy by network pharmacology

et al. 2019

Preprint

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“…Due to low incidence of the mutation, effects of novel antileukemic agents and of allogeneic HSCT in this class of AML can only assessed in intergroup trials or in retrospective large meta-analyses. Moreover new research identified histone deacetylase (HDAC) inhibitors are able to reactivate the expression of the CEBPA signature and enhance the growth of healthy blood cells, showing the HDAC inhibitors as potential drug targets for the treatment of the AML subtype [79]. Another finding identified and validate a gene Sox4, molecular target for CEBPA mutations, targeting Sox4 effectively inhibits the major leukemogenic phenotypes in human mutated CEBPA AML samples [80].…”

Section: Cebpa Therapeutic Implicationmentioning

confidence: 99%

Distinct Gene Mutations, their Prognostic Relevance and Molecularly Targeted Therapies in Acute Myeloid Leukemia (AML)

Tayyab¹

2014

J Cancer Sci Ther

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Acquired genetic alterations which include balanced and unbalanced chromosome aberrations and submicroscopic gene mutations and changes in gene expression strongly influenced by pretreatment clinical features and prognosis of adults patients with acute myeloid leukemia (AML). Cytogenetic profiling separate AML patients into three broad prognostic groups: favorable, intermediate and adverse. The cytogenetic risk classifications vary to some extent for younger adult patients and for those aged 60 years or older. In many cases, patients with specific cytogenetic rearrangement such as those with a normal karyotype or those with either RUNX1-RUNX1T1 or CBFB-MYH11 feature of core-binding factor (CBF) can be further subdivided into prognostic categories depend on the presence or absence of specific gene mutations or changes in gene expression. Advancement in the understanding of cancer genetic and discovery of recurrent mutations in AML provide opportunity to develop targeted therapies and improve the clinical outcome. The identified gene mutations, mainly targetable lesions are gain of function mutations of JAK2 and cKIT and FLT3 in APL have been associated with clinical features and/ or outcome of patients with these AML subtypes. These data emphasize the significance of genetic testing for common translocations for diagnosis, prognosis and increasingly targeted therapy in acute leukemia. Notably, these several molecular genetic alterations constitute a variety of diverse new targets for salvage therapies. These approaches intend to develop targeted treatment concepts that depend on interference with molecular genetics or epigenetic mechanisms. This report provides an overview on characteristic gene mutations, discuss their biological functions and Prognostic significance, which serve as basis for selected therapy approaches now or might represent options for such approaches in the future and expected to have a role in treating AML subtypes with characteristic molecular alterations.

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“…Histone deacetylase inhibitors (HDACi) have the potential to exert antitumor effects (7) and thus represent an important therapeutic alternative for cases of AML (8,9). HDACi exert their anticancer effects through a variety of mechanisms, including stress-related pathway activation, protective pathway inhibition, death receptor upregulation, ceramide generation, heat shock protein accumulation, as well as oxidative damage collapse (10).…”

Section: Introductionmentioning

confidence: 99%

“…VPA also regulates tumor growth, thus affecting different cell properties, including proliferation, differentiation, tumor metastasis, tumor immunogenicity and angiogenesis; one important finding is that VPA functions as an HDACi, possibly by binding to the catalytic centre of HDACs (12). Several previous studies have shown that VPA has a broad impact on AML blast cells by inhibiting HDAC class Ⅰ activity, and this effect is usually accompanied by increased levels of histone H3 and H4 acetylation (7)(8)(9)(10). Cytarabine (Ara-C) is a chemotherapeutic drug that is used alone or in combination with other traditional antileukemic regimens to treat different forms of AML.…”

Section: Introductionmentioning

confidence: 99%

Valproic acid enhances the antileukemic effect of cytarabine by triggering cell apoptosis

Liu

Wang

et al. 2016

International Journal of Molecular Medicine

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Abstract. Acute myeloid leukemia (AML) is an aggressive clonal malignancy of hematopoietic progenitor cells with a poor clinical outcome. The resistance of leukemia cells to contemporary chemotherapy is one of the most formidable obstacles to treating AML. Combining valproic acid (VPA) with other anti-leukemic agents has previously been noted as a useful and necessary strategy which can be used to specifically induce anticancer gene expression. In the present study, we demonstrated the synergistic antileukemic activities between VPA and cytarabine (Ara-C) in a retrovirus-mediated murine model with MLL-AF9 leukemia, three leukemia cell lines (THP-1, K562 and HL-60) and seven primary human AML samples. Using RT-qPCR, we noted that the combination of VPA and Ara-C significantly upregulated BAX expression and led to the arrest of leukemia cell proliferation, sub-G1 DNA accumulation and cell apoptosis, as demonstrated by flow cytometric analysis. Significantly, further experiments revealed that knockdown of BAX expression prevented VPA and Ara-C-induced cell apoptosis in THP-1 cells. The results of our present study demonstrated the synergistic antileukemic effect of combined VPA and Ara-C treatment in AML, and thus we suggest that VPA be used an alternative treatment for AML.

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The gene signature in CCAAT-enhancer-binding protein dysfunctional acute myeloid leukemia predicts responsiveness to histone deacetylase inhibitors

Cited by 14 publications

References 46 publications

Identification of drugs for leukaemia differentiation therapy by network pharmacology

Identification of drugs for leukaemia differentiation therapy by network pharmacology

Distinct Gene Mutations, their Prognostic Relevance and Molecularly Targeted Therapies in Acute Myeloid Leukemia (AML)

Valproic acid enhances the antileukemic effect of cytarabine by triggering cell apoptosis

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