Perivascular mesenchymal stem and progenitor cells (MSPCs) are critical for forming a healthy hematopoietic stem cell (HSC) niche. However, the interactions and influence of acute myelogenous ...leukemia (AML) stem cells with the microenvironment remain largely unexplored. We have unexpectedly found that neuropathy of the sympathetic nervous system (SNS) promotes leukemic bone marrow infiltration in an MLL-AF9 AML model. Development of AML disrupts SNS nerves and the quiescence of Nestin+ niche cells, leading to an expansion of phenotypic MSPCs primed for osteoblastic differentiation at the expense of HSC-maintaining NG2+ periarteriolar niche cells. Adrenergic signaling promoting leukemogenesis is transduced by the β2, but not β3, adrenergic receptor expressed on stromal cells of leukemic bone marrow. These results indicate that sympathetic neuropathy may represent a mechanism for the malignancy in order to co-opt the microenvironment and suggest separate mesenchymal niche activities for malignant and healthy hematopoietic stem cells in the bone marrow.
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•AML leads to sympathetic neuropathy and expansion of an altered bone marrow niche•MSC differentiation is enhanced toward osteoprogenitors with maturation arrest•AML reduces NG2+ cell numbers and HSC niche regulating activity•Sympathetic neuropathy promotes AML through stromal Adrβ2
Development of acute myelogenous leukemia (AML) disrupts sympathetic nerves and the quiescence of Nestin+ niche cells, enhancing expansion of phenotypic mesenchymal stem/progenitor cells primed for osteoblastic differentiation at the expense of HSC-maintaining NG2+ periarteriolar niche cells.
Pinometostat (EPZ-5676) is a first-in-class small-molecule inhibitor of the histone methyltransferase disrupter of telomeric silencing 1-like (DOT1L). In this phase 1 study, pinometostat was ...evaluated for safety and efficacy in adult patients with advanced acute leukemias, particularly those involving mixed lineage leukemia (MLL) gene rearrangements (MLL-r) resulting from 11q23 translocations. Fifty-one patients were enrolled into 6 dose-escalation cohorts (n = 26) and 2 expansion cohorts (n = 25) at pinometostat doses of 54 and 90 mg/m2 per day by continuous intravenous infusion in 28-day cycles. Because a maximum tolerated dose was not established in the dose-escalation phase, the expansion doses were selected based on safety and clinical response data combined with pharmacodynamic evidence of reduction in H3K79 methylation during dose escalation. Across all dose levels, plasma pinometostat concentrations increased in an approximately dose-proportional fashion, reaching an apparent steady-state by 4-8 hours after infusion, and rapidly decreased following treatment cessation. The most common adverse events, of any cause, were fatigue (39%), nausea (39%), constipation (35%), and febrile neutropenia (35%). Overall, 2 patients, both with t(11;19), experienced complete remission at 54 mg/m2 per day by continuous intravenous infusion, demonstrating proof of concept for delivering clinically meaningful responses through targeting DOT1L using the single agent pinometostat in MLL-r leukemia patients. Administration of pinometostat was generally safe, with the maximum tolerated dose not being reached, although efficacy as a single agent was modest. This study demonstrates the therapeutic potential for targeting DOT1L in MLL-r leukemia and lays the groundwork for future combination approaches in this patient population. This clinical trial is registered at www.clinicaltrials.gov as NCT01684150.
•Pinometostat demonstrates first evidence of DOT1L target inhibition and clinical responses in a subset of MLL-r advanced leukemia patients.•The observed safety profile of pinometostat shows potential for exploration of combination therapies in leukemia.
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The epigenome is a key determinant of transcriptional output. Perturbations within the epigenome are thought to be a key feature of many, perhaps all cancers, and it is now clear that epigenetic ...changes are instrumental in cancer development. The inherent reversibility of these changes makes them attractive targets for therapeutic manipulation, and a number of small molecules targeting chromatin-based mechanisms are currently in clinical trials. In this perspective we discuss how understanding the cancer epigenome is providing insights into disease pathogenesis and informing drug development. We also highlight additional opportunities to further unlock the therapeutic potential within the cancer epigenome.
In this perspective article Brien et al. discuss how our burgeoning understanding of the epigenetic changes in cancer is providing significant insights into the mechanistic role of the epigenome in oncogenesis. Moreover, the authors highlight how this understanding is being exploited therapeutically with the development of novel epigenetic therapies, several of which are in ongoing clinical trials. Finally, the authors discuss possibilities to further unlock the therapeutic potential within the cancer epigenome, through efforts to broaden our understanding of the epigenetic changes underlying cancer development.
MLL/SET methyltransferases catalyze methylation of histone 3 lysine 4 and play critical roles in development and cancer. We assessed MLL/SET proteins and found that SETD1A is required for survival of ...acute myeloid leukemia (AML) cells. Mutagenesis studies and CRISPR-Cas9 domain screening show the enzymatic SET domain is not necessary for AML cell survival but that a newly identified region termed the “FLOS” (functional location on SETD1A) domain is indispensable. FLOS disruption suppresses DNA damage response genes and induces p53-dependent apoptosis. The FLOS domain acts as a cyclin-K-binding site that is required for chromosomal recruitment of cyclin K and for DNA-repair-associated gene expression in S phase. These data identify a connection between the chromatin regulator SETD1A and the DNA damage response that is independent of histone methylation and suggests that targeting SETD1A and cyclin K complexes may represent a therapeutic opportunity for AML and, potentially, for other cancers.
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•H3K4 methyltransferase SETD1A has non-redundant functions with SETD1B•Non-enzymatic domain of SETD1A is indispensable for leukemia cell growth•The SETD1A FLOS domain regulates expression of genes involved in DNA damage response•The SETD1A FLOS domain interacts with cyclin K to regulate gene expression
Independent of its enzymatic activity, H3K4 methyltransferase SETD1A promotes leukemic cell survival by regulating DNA damage response.
The bromodomain‐containing protein BRD9, a subunit of the human BAF (SWI/SNF) nucleosome remodeling complex, has emerged as an attractive therapeutic target in cancer. Despite the development of ...chemical probes targeting the BRD9 bromodomain, there is a limited understanding of BRD9 function beyond acetyl‐lysine recognition. We have therefore created the first BRD9‐directed chemical degraders, through iterative design and testing of heterobifunctional ligands that bridge the BRD9 bromodomain and the cereblon E3 ubiquitin ligase complex. Degraders of BRD9 exhibit markedly enhanced potency compared to parental ligands (10‐ to 100‐fold). Parallel study of degraders with divergent BRD9‐binding chemotypes in models of acute myeloid leukemia resolves bromodomain polypharmacology in this emerging drug class. Together, these findings reveal the tractability of non‐BET bromodomain containing proteins to chemical degradation, and highlight lead compound dBRD9 as a tool for the study of BRD9.
With structural guidance alongside comparative biochemical and biological assays, an iterative design strategy resulted in the development of small‐molecule protein degraders that rapidly, potently, and selectively eliminate bromodomain‐containing protein BRD9 from the BAF complex. These first in class non‐BET bromodomain degraders show significant potency improvements over existing BRD9 probes in models of acute myeloid leukemia.
Neuromarketing is an emerging field in which academic and industry research scientists employ neuroscience techniques to study marketing practices and consumer behavior. The use of neuroscience ...techniques, it is argued, facilitates a more direct understanding of how brain states and other physiological mechanisms are related to consumer behavior and decision making. Herein, we will articulate common ethical concerns with neuromarketing as currently practiced, focusing on the potential risks to consumers and the ethical decisions faced by companies. We argue that the most frequently raised concerns—threats to consumer autonomy, privacy, and control—do not rise to meaningful ethical issues given the current capabilities and implementation of neuromarketing research. But, we identify how potentially serious ethical issues may emerge from neuromarketing research practices in industry, which are largely proprietary and opaque. We identify steps that can mitigate associated ethical risks and thus reduce the threats to consumers. We conclude that neuromarketing has clear potential for positive impact on society and consumers, a fact rarely considered in the discussion on the ethics of neuromarketing.
Mislocated enzymatic activity of DOT1L has been proposed as a driver of leukemogenesis in mixed lineage leukemia (MLL). The characterization of EPZ004777, a potent, selective inhibitor of DOT1L is ...reported. Treatment of MLL cells with the compound selectively inhibits H3K79 methylation and blocks expression of leukemogenic genes. Exposure of leukemic cells to EPZ004777 results in selective killing of those cells bearing the
MLL gene translocation, with little effect on non-
MLL-translocated cells. Finally, in vivo administration of EPZ004777 leads to extension of survival in a mouse MLL xenograft model. These results provide compelling support for DOT1L inhibition as a basis for targeted therapeutics against MLL.
► A potent and selective inhibitor of DOT1L enzymatic activity has been designed ► The inhibitor blocks H3K79 methylation and selectively kills
MLL-rearranged cells ► The inhibitor demonstrates antileukemia activity in a xenograft model of MLL ► These data validate the use of DOT1L inhibitors as targeted therapeutics for MLL
Activating mutations in PIK3CA, the gene encoding phosphoinositide-(3)-kinase α (PI3Kα), are frequently found in estrogen receptor (ER)–positive breast cancer. PI3Kα inhibitors, now in late-stage ...clinical development, elicit a robust compensatory increase in ER-dependent transcription that limits therapeutic efficacy. We investigated the chromatin-based mechanisms leading to the activation of ER upon PI3Kα inhibition. We found that PI3Kα inhibition mediates an open chromatin state at the ER target loci in breast cancer models and clinical samples. KMT2D, a histone H3 lysine 4 methyltransferase, is required for FOXA1, PBX1, and ER recruitment and activation. AKT binds and phosphorylates KMT2D, attenuating methyltransferase activity and ER function, whereas PI3Kα inhibition enhances KMT2D activity. These findings uncover a mechanism that controls the activation of ER by the posttranslational modification of epigenetic regulators, providing a rationale for epigenetic therapy in ER-positive breast cancer.
Enhancer activation is a critical step for gene activation. Here we report an epigenetic crosstalk at enhancers between the UTX (H3K27 demethylase)-MLL4 (H3K4 methyltransferase) complex and the ...histone acetyltransferase p300. We demonstrate that UTX, in a demethylase activity-independent manner, facilitates conversion of inactive enhancers in embryonic stem cells to an active (H3K4me1+/H3K27ac+) state by recruiting and coupling the enzymatic functions of MLL4 and p300. Loss of UTX leads to attenuated enhancer activity, characterized by reduced levels of H3K4me1 and H3K27ac as well as impaired transcription. The UTX-MLL4 complex enhances p300-dependent H3K27 acetylation through UTX-dependent stimulation of p300 recruitment, while MLL4-mediated H3K4 monomethylation, reciprocally, requires p300 function. Importantly, MLL4-generated H3K4me1 further enhances p300-dependent transcription. This work reveals a previously unrecognized cooperativity among enhancer-associated chromatin modulators, including a unique function for UTX, in establishing an “active enhancer landscape” and defines a detailed mechanism for the joint deposition of H3K4me1 and H3K27ac.
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•UTX drives a feedforward regulatory loop in setting up active enhancer landscapes•Direct UTX interactions facilitate recruitment and cooperativity of MLL4 and p300•The UTX demethylase activity is not required for setting up active enhancers•Disruption of UTX, MLL4, or p300 impedes maintenance of active enhancers
Wang et al. report a crosstalk at enhancers between the UTX (H3K27 demethylase)-MLL4 (H3K4 methyltransferase) complex and the histone acetyltransferase p300. UTX, in a demethylase activity-independent manner, facilitates conversion of inactive enhancers in ESCs to an active (H3K4me1+/H3K27ac+) state by recruiting and coupling the functions of MLL4 and p300.
Translocations that involve the mixed lineage leukaemia (MLL) gene identify a unique group of acute leukaemias, and often predict a poor prognosis. The MLL gene encodes a DNA-binding protein that ...methylates histone H3 lysine 4 (H3K4), and positively regulates gene expression including multiple Hox genes. Leukaemogenic MLL translocations encode MLL fusion proteins that have lost H3K4 methyltransferase activity. A key feature of MLL fusion proteins is their ability to efficiently transform haematopoietic cells into leukaemia stem cells. The link between a chromatin modulator and leukaemia stem cells provides support for epigenetic landscapes as an important part of leukaemia and normal stem-cell development.
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