Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Genome-wide chromatin maps of T-cell acute lymphoblastic leukemia (T-ALL) [ChIP-seq]

ABSTRACT: Here we modeled T-ALL resistance to Notch inhibition, identifying M-bM-^@M-^XpersisterM-bM-^@M-^Y cells that readily expand in the presence of gamma secretase inhibitor (GSI) and the absence of Notch signaling. Rare persister cells are already present in naM-CM-/ve T-ALL populations, and the reversibility of the phenotype is suggestive of an epigenetic mechanism. Relative to GSI-sensitive cells, persisters activate distinct signaling and gene expression programs, and exhibit global chromatin compaction. A shRNA screen identified chromatin regulators whose depletion preferentially impairs persister cell viability, including BRD4, an acetyl-histone reader. BRD4 is up-regulated in the persisters and binds enhancers near genes with critical functions in T-ALL, including MYC and BCL2. Treatment of persisters with the BRD4 inhibitor JQ1 down-regulates these targets and induces growth arrest and apoptosis, at doses well tolerated by GSI-sensitive cells. Prompted by these findings, we examined and established the efficacy of GSI M-bM-^@M-^S JQ1 combination therapy against primary human leukemias in vivo. Our findings establish a role for epigenetic heterogeneity in leukemia drug resistance and suggest the potential of combination therapies that include epigenetic modulators to prevent and treat resistant disease. Examination of 5 different histone modifications and BRD4 in the T cell leukemia cell lines DND-41 and KOPT-K1 after chronic treatment with gamma Secretase inhibitor (Compound E, 1 uM, EMD4 Bioscience; persister) or vehicle (naM-CM-/ve).

ORGANISM(S): Homo sapiens

SUBMITTER: Jiang Zhu

PROVIDER: E-GEOD-54379 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia.

Knoechel Birgit B Roderick Justine E JE Williamson Kaylyn E KE Zhu Jiang J Lohr Jens G JG Cotton Matthew J MJ Gillespie Shawn M SM Fernandez Daniel D Ku Manching M Wang Hongfang H Piccioni Federica F Silver Serena J SJ Jain Mohit M Pearson Daniel D Kluk Michael J MJ Ott Christopher J CJ Shultz Leonard D LD Brehm Michael A MA Greiner Dale L DL Gutierrez Alejandro A Stegmaier Kimberly K Kung Andrew L AL Root David E DE Bradner James E JE Aster Jon C JC Kelliher Michelle A MA Bernstein Bradley E BE

Nature genetics 20140302 4

The identification of activating NOTCH1 mutations in T cell acute lymphoblastic leukemia (T-ALL) led to clinical testing of γ-secretase inhibitors (GSIs) that prevent NOTCH1 activation. However, responses to these inhibitors have been transient, suggesting that resistance limits their clinical efficacy. Here we modeled T-ALL resistance, identifying GSI-tolerant 'persister' cells that expand in the absence of NOTCH1 signaling. Rare persisters are already present in naive T-ALL populations, and th ...[more]

PMID: 24584072

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Project description:Staphylococcus aureus causes invasive infections and easily acquires antibiotic resistances. Even antibiotic susceptible S. aureus can survive antibiotic therapy and persist, requiring prolonged treatment and surgical interventions. These so-called persisters display an arrested-growth phenotype, tolerate high antibiotic concentrations and are associated with chronic and recurrent infections. To characterize these persisters, we assessed S. aureus recovered directly from a patient suffering from a persistent infection. We show that host-mediated stress, including acidic-pH, abscesses-environment, and antibiotic exposure promoted persister formation in-vitro and in-vivo. Multi-omics analysis identified molecular changes in S. aureus in response to acid-stress leading to an overall virulent population. However, further analysis of a persister-enriched population revealed major molecular reprogramming in persisters including downregulation of virulence and cell division, and upregulation of ribosomal proteins, nucleotide-, and amino acid- metabolic pathways, suggesting their requirement to fuel and maintain the persister phenotype and highlighting that persisters are not completely metabolically inactive. Additionally, decreased aconitase activity and ATP-levels and accumulation of insoluble proteins involved in transcription, translation and energy-production correlated with persistence in S. aureus, underpinning the molecular mechanisms that drive the persister phenotype. Upon regrowth, these persisters regained their virulence potential and metabolically active phenotype including reduction of insoluble proteins, exhibiting a reversible state, crucial for recurrent infections. We further show that a targeted anti-persister combination therapy using retinoid derivatives and antibiotics significantly reduced lag-phase heterogeneity and persisters in a murine infection model. Our results provide molecular insights into persisters and help explain why persistent S. aureus infections are so difficult-to-treat.

Dataset Information

Genome-wide chromatin maps of T-cell acute lymphoblastic leukemia (T-ALL) [ChIP-seq]

Publications

An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia.

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