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Whole Genome Sequencing of Candida glabrata for Detection of Markers of Antifungal Drug Resistance
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An Integrated Genome-wide CRISPRa Approach to Functionalize lncRNAs in Drug Resistance

Assaf C Bester1, Jonathan D Lee1, Alejandro Chavez2

  • 1Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.

Cell
|April 21, 2018
PubMed

Insights

This study introduces a new CRISPR screening platform (DICaS) to find genes impacting cancer drug resistance. It identified novel cell-cycle, survival, and signaling genes, including GAS6-AS2 lncRNA, which contributes to chemotherapy resistance in AML.

Area of Science:

  • Genomics
  • Molecular Biology
  • Cancer Research

Background:

  • Chemotherapy resistance is a major cause of cancer mortality.
  • Cytarabine is a key treatment for acute myeloid leukemia (AML).
  • Identifying genetic factors influencing drug sensitivity is crucial for improving cancer therapy.

Purpose of the Study:

  • To develop and apply a comprehensive genome-wide CRISPR activation screening platform (DICaS) to identify genetic determinants of cytarabine sensitivity in cancer.
  • To functionally characterize both protein-coding and long non-coding RNA (lncRNA) genes involved in drug resistance.
  • To uncover novel therapeutic targets and resistance mechanisms in AML and other cancers.

Main Methods:

  • Development of a dual protein-coding and non-coding integrated CRISPR activation screening (DICaS) platform.
  • Initial identification of putative resistance genes using pharmacogenetic data from 760 human pan-cancer cell lines.
  • Genome-wide functional characterization of coding and lncRNA genes using CRISPR activation, including a specific CRISPR activation of lncRNA (CaLR) strategy for 14,701 lncRNA genes.

Main Results:

  • DICaS successfully identified novel genes associated with cell-cycle regulation, survival/apoptosis, and cancer signaling pathways.
  • Transcriptional activation of the identified GAS6-AS2 lncRNA was shown to hyperactivate the GAS6/TAM pathway.
  • This hyperactivation represents a significant resistance mechanism in multiple cancers, including AML.

Conclusions:

  • The DICaS platform is a powerful and integrated approach for discovering therapeutic targets by analyzing both coding and non-coding genetic elements.
  • The findings highlight the role of lncRNAs, such as GAS6-AS2, in mediating chemotherapy resistance.
  • This research provides new insights into the genetic basis of cytarabine resistance and offers potential strategies for overcoming it in AML and other malignancies.
Keywords:
AMLAXL/GAS6CRISPRCRISPRaTEMcancercytarabinedrug-resistanceleukemialncRNA

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