Reference Detail

Ref Type Journal Article
PMID (27443263)
Authors Cruickshank MN, Ford J, Cheung LC, Heng J, Singh S, Wells J, Failes TW, Arndt GM, Smithers N, Prinjha RK, Anderson D, Carter KW, Gout AM, Lassmann T, O'Reilly J, Cole CH, Kotecha RS, Kees UR
Title Systematic chemical and molecular profiling of MLL-rearranged infant acute lymphoblastic leukemia reveals efficacy of romidepsin.
Journal Leukemia
Vol 31
Issue 1
Date 2017 Jan
URL
Abstract Text To address the poor prognosis of mixed lineage leukemia (MLL)-rearranged infant acute lymphoblastic leukemia (iALL), we generated a panel of cell lines from primary patient samples and investigated cytotoxic responses to contemporary and novel Food and Drug Administration-approved chemotherapeutics. To characterize representation of primary disease within cell lines, molecular features were compared using RNA-sequencing and cytogenetics. High-throughput screening revealed variable efficacy of currently used drugs, however identified consistent efficacy of three novel drug classes: proteasome inhibitors, histone deacetylase inhibitors and cyclin-dependent kinase inhibitors. Gene expression of drug targets was highly reproducible comparing iALL cell lines to matched primary specimens. Histone deacetylase inhibitors, including romidepsin (ROM), enhanced the activity of a key component of iALL therapy, cytarabine (ARAC) in vitro and combined administration of ROM and ARAC to xenografted mice further reduced leukemia burden. Molecular studies showed that ROM reduces expression of cytidine deaminase, an enzyme involved in ARAC deactivation, and enhances the DNA damage-response to ARAC. In conclusion, we present a valuable resource for drug discovery, including the first systematic analysis of transcriptome reproducibility in vitro, and have identified ROM as a promising therapeutic for MLL-rearranged iALL.

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
KMT2A rearrange acute lymphocytic leukemia decreased response Romidepsin Preclinical - Cell line xenograft Actionable In a preclinical study, Istodax (romidepsin) resulted in minimal activity in acute lymphocytic leukemia cell lines harboring a KMT2A rearrangement in culture, and in cell line xenograft models, demonstrating decreased leukemic cells by 16% (PMID: 27443263). 27443263
KMT2A rearrange acute lymphocytic leukemia sensitive Cytarabine + Romidepsin Preclinical - Cell line xenograft Actionable In a preclinical study, Istodax (romidepsin) enhanced the effects of Cytosar-U (cytarabine) in acute lymphocytic leukemia cell lines harboring a KMT2A rearrangement in culture, and in cell line xenograft models, demonstrating decreased leukemic cells by 73% (PMID: 27443263). 27443263
KMT2A rearrange acute lymphocytic leukemia sensitive Cytarabine + Dacinostat Preclinical - Cell culture Actionable In a preclinical study, Dacinostat (LAQ824) enhanced the effects of Cytosar-U (cytarabine) in acute lymphoblastic leukemia cell lines harboring a KMT2A rearrangement in culture, resulting in cell death (PMID: 27443263). 27443263
KMT2A rearrange acute lymphocytic leukemia sensitive Cytarabine + Panobinostat Preclinical - Cell culture Actionable In a preclinical study, Farydak (panobinostat) enhanced the effects of Cytosar-U (cytarabine) in acute lymphoblastic leukemia cells harboring a KMT2A rearrangement in culture, resulting in cell death (PMID: 27443263). 27443263
KMT2A rearrange acute lymphocytic leukemia sensitive Cytarabine + Mocetinostat Preclinical - Cell culture Actionable In a preclinical study, Mocetinostat (MGCD0103) enhanced the effects of Cytosar-U (cytarabine) in acute lymphoblastic leukemia cell lines harboring a KMT2A rearrangement in culture, resulting in cell death (PMID: 27443263). 27443263
KMT2A rearrange acute lymphocytic leukemia sensitive Cytarabine Preclinical - Cell line xenograft Actionable In a preclinical study, Cytosar-U (cytarabine) decreased leukemic cells by 66% in acute lymphocytic leukemia cell line xenograft models harboring a KMT2A rearrangement (PMID: 27443263). 27443263