Genome-wide chromatin maps of T-cell acute lymphoblastic leukemia (T-ALL)
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Jiang Zhu
PROVIDER: E-GEOD-54380 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description: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 gene expression profiles 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). 2 replicates in each group.
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