Acute myeloid leukemia (AML) is the most common form of adult leukemia. The transcription factor fusion CBFβ-SMMHC (core binding factor β and the smooth-muscle myosin heavy chain), expressed in AML with the chromosome inversion inv(16)(p13q22), outcompetes wild-type CBFβ for binding to the transcription factor RUNX1, deregulates RUNX1 activity in hematopoiesis, and induces AML. Current inv(16) AML treatment with nonselective cytotoxic chemotherapy results in a good initial response but limited long-term survival. Here, we report the development of a protein-protein interaction inhibitor, AI-10-49, that selectively binds to CBFβ-SMMHC and disrupts its binding to RUNX1. AI-10-49 restores RUNX1 transcriptional activity, displays favorable pharmacokinetics, and delays leukemia progression in mice. Treatment of primary inv(16) AML patient blasts with AI-10-49 triggers selective cell death. These data suggest that direct inhibition of the oncogenic CBFβ-SMMHC fusion protein may be an effective therapeutic approach for inv(16) AML, and they provide support for transcription factor targeted therapy in other cancers.
We have previously shown that the plantderived compound parthenolide (PTL) can impair the survival and leukemogenic activity of primary human acute myeloid leukemia (AML) stem cells. However, despite the activity of this agent, PTL also induces cellular protective responses that likely function to reduce its overall cytotoxicity. Thus, we sought to identify pharmacologic agents that enhance the antileukemic potential of PTL. IntroductionThe biologic heterogeneity within primary human tumors has become an increasingly prevalent consideration for the development of new therapies. 1,2 This heterogeneity is evident for acute myeloid leukemia (AML) in which the data suggest that a subpopulation of the bulk AML, the AML stem cells (AML-SCs), are essential for initiating and perpetuating disease as well as resistance to standard chemotherapy, likely providing a residual cell population that promotes relapse. [3][4][5][6][7] Toward improving clinical outcomes, we and others have proposed and devised therapies that effectively circumvent the resistance of AML-SCs in preclinical studies. [5][6][7][8] Indeed, previous studies demonstrated that agents capable of simultaneously inhibiting nuclear factor-B (NF-B) and inducing oxidative stress were effective for ablation of AML-SCs. Both of these functions are performed by the single agent, parthenolide (PTL). However, PTL is a suboptimal pharmaceutical, and concentrations of PTL required to ablate AML-SCs are not likely to be achievable in patients. 8 This limitation has prompted efforts to discover pharmacologically superior analogs such as dimethyl-amino-parthenolide (DMAPT), which is currently in clinical trials. 9 In addition, in silico gene expression-based screens using the PTL transcriptional signature as a template have identified compounds such as celastrol 10 and 4-hydroxy-2-nonenal 11-15 that demonstrate PTL-like mechanistic and functional properties. 16 Here, we hypothesized that chemical genomic approaches can predict compounds that are likely to enhance the efficacy of PTL or DMAPT. To test this hypothesis, we performed chemical genomic screening against the recently expanded Connectivity Map chemogenomic database build02 (CMap2), which now includes 6100 chemical perturbations of cancer cells and represents the most substantial repository of chemogenomic data, allowing for exploration of relationships between compounds on the basis of transcriptional profiles (reviewed in Lamb et al 17 ). Several recent studies indicate the ability of chemical genomics to recapitulate and/or modulate chemical and biologic processes that are relevant to therapy through comparison of gene expression patterns. 10,16,[18][19][20] Since the PTL transcriptional signature is enriched for cytoprotective pathways that likely decrease the potency of PTL, we used the Connectivity Map database to identify compounds that impair this cytoprotection and enhance the efficacy of PTL. We discovered compounds acting along the PI3K and mTOR pathways. MethodsCompounds, primary tissue, and cell cult...
SUMMARYAcute myeloid leukemia (AML) is a heterogeneous and fatal disease with an urgent need for improved therapeutic regimens given that most patients die from relapsed disease. Irrespective of mutation status, the development of aggressive leukemias is enabled by increasing dependence on signaling networks. We demonstrate that a hyperactive signalosome drives addiction of AML cells to a tumor-specific Hsp90 species (teHsp90). Through genetic, environmental, and pharmacologic perturbations, we demonstrate a direct and quantitative link between hyperactivated signaling pathways and apoptotic sensitivity of AML to teHsp90 inhibition. Specifically, we find that hyperactive JAK-STAT and PI3K-AKT signaling networks are maintained by teHsp90 and, in fact, gradual activation of these networks drives tumors increasingly dependent on teHsp90. Thus, although clinically aggressive AML survives via signalosome activation, this addiction creates a vulnerability that can be exploited with Hsp90-directed therapy.
Ciclopirox, an antifungal agent commonly used for the dermatologic treatment of mycoses, has been shown recently to have antitumor properties. Although the exact mechanism of ciclopirox is unclear, its antitumor activity has been attributed to iron chelation and inhibition of the translation initiation factor eIF5A. In this study, we identify a novel function of ciclopirox in the inhibition of mTOR. As with other mTOR inhibitors, we show that ciclopirox significantly enhances the ability of the established preclinical antileukemia compound, parthenolide, to target acute myeloid leukemia. The combination of parthenolide and ciclopirox demonstrates greater toxicity against acute myeloid leukemia than treatment with either compound alone. We also demonstrate that the ability of ciclopirox to inhibit mTOR is specific to ciclopirox because neither iron chelators nor other eIF5A inhibitors affect mTOR activity, even at high doses. We have thus identified a novel function of ciclopirox that might be important for its antileukemic activity.
Background: The mammalian protein kinase TLK1 is a homologue of Tousled, a gene involved in flower development in Arabidopsis thaliana. The function of TLK1 is not well known, although knockout of the gene in Drosophila, or expression of a dominant negative mutant in mouse mammary cells causes loss of nuclear divisions and chromosome mis-segregation. TLK1B is a splice variant of TLK1 and it confers radioresistance in a normal mammary mouse cell line possibly due to increased chromatin remodeling capacity, but the mechanism of resistance remains to be fully elucidated.
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