Reference Detail

Ref Type Journal Article
PMID (27630125)
Authors Scott MT, Korfi K, Saffrey P, Hopcroft LE, Kinstrie R, Pellicano F, Guenther C, Gallipoli P, Cruz M, Dunn K, Jorgensen HG, Cassels JE, Hamilton A, Crossan A, Sinclair A, Holyoake TL, Vetrie D
Title Epigenetic Reprogramming Sensitizes CML Stem Cells to Combined EZH2 and Tyrosine Kinase Inhibition.
Journal Cancer discovery
Vol 6
Issue 11
Date 2016 Nov
URL
Abstract Text A major obstacle to curing chronic myeloid leukemia (CML) is residual disease maintained by tyrosine kinase inhibitor (TKI)-persistent leukemic stem cells (LSC). These are BCR-ABL1 kinase independent, refractory to apoptosis, and serve as a reservoir to drive relapse or TKI resistance. We demonstrate that Polycomb Repressive Complex 2 is misregulated in chronic phase CML LSCs. This is associated with extensive reprogramming of H3K27me3 targets in LSCs, thus sensitizing them to apoptosis upon treatment with an EZH2-specific inhibitor (EZH2i). EZH2i does not impair normal hematopoietic stem cell survival. Strikingly, treatment of primary CML cells with either EZH2i or TKI alone caused significant upregulation of H3K27me3 targets, and combined treatment further potentiated these effects and resulted in significant loss of LSCs compared to TKI alone, in vitro, and in long-term bone marrow murine xenografts. Our findings point to a promising epigenetic-based therapeutic strategy to more effectively target LSCs in patients with CML receiving TKIs.In CML, TKI-persistent LSCs remain an obstacle to cure, and approaches to eradicate them remain a significant unmet clinical need. We demonstrate that EZH2 and H3K27me3 reprogramming is important for LSC survival, but renders LSCs sensitive to the combined effects of EZH2i and TKI. This represents a novel approach to more effectively target LSCs in patients receiving TKI treatment. Cancer Discov; 6(11); 1248-57. ©2016 AACR.See related article by Xie et al., p. 1237This article is highlighted in the In This Issue feature, p. 1197.

Filtering

  • Case insensitive filtering will display rows where any text in any cell matches the filter term
  • Simple literal full or partial string matches
  • Separate multiple filter terms with a spaces, order doesn't matter (a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page, filtering has no impact on query parameters
  • Use quotes to match a longer phrase which contains spaces "mtor c1483f"

Sorting

  • Generally, the default sort order for tables is set to be first column ascending, however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column, be sure to set ascending or descending order for a given column, before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown chronic myeloid leukemia not applicable Nilotinib + Tazemetostat Preclinical Actionable In a preclinical study, treatment with the combination of Tasigna (Nilotinib) and EPZ-6438 resulted in decreased levels of leukemic cells and progenitors in primary chronic myeloid leukemia cell xenograft models, with increased efficacy compared to Tasigna (Nilotinib) alone (PMID: 27630125). 27630125
Unknown unknown chronic myeloid leukemia not applicable Dasatinib + GSK343 Preclinical - Patient cell culture Actionable In a preclinical study, the combination of Sprycel (dasatinib) and GSK343 resulted in increased apoptosis and reduced viability of human primary chronic myeloid leukemia cells in culture, compared to Sprycel (dasatinib) alone (PMID: 27630125). 27630125
Unknown unknown chronic myeloid leukemia not applicable GSK343 Preclinical - Patient cell culture Actionable In a preclinical study, GSK343 decreased H3K27 trimethylation, and reduced viability and increased apoptosis of primary chronic myeloid leukemia cells in culture (PMID: 27630125). 27630125