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Investigation of Genetic Dependencies Using CRISPR-Cas9-based Competition Assays
Published on: January 7, 2019
A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia
Konstantinos Tzelepis1, Hiroko Koike-Yusa1, Etienne De Braekeleer1
1Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
Abstract:
Acute myeloid leukemia (AML) is an aggressive cancer with a poor prognosis, for which mainstream treatments have not changed for decades. To identify additional therapeutic targets in AML, we optimize a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screening platform and use it to identify genetic vulnerabilities in AML cells. We identify 492 AML-specific cell-essential genes, including several established therapeutic targets such as DOT1L, BCL2, and MEN1, and many other genes including clinically actionable candidates. We validate selected genes using genetic and pharmacological inhibition, and chose KAT2A as a candidate for downstream study. KAT2A inhibition demonstrated anti-AML activity by inducing myeloid differentiation and apoptosis, and suppressed the growth of primary human AMLs of diverse genotypes while sparing normal hemopoietic stem-progenitor cells. Our results propose that KAT2A inhibition should be investigated as a therapeutic strategy in AML and provide a large number of genetic vulnerabilities of this leukemia that can be pursued in downstream studies.
Insights
Researchers identified KAT2A as a potential therapeutic target for acute myeloid leukemia (AML). Inhibiting KAT2A shows promise in treating AML by inducing cell death and differentiation while sparing healthy cells.
Area of Science:
- Hematology
- Oncology
- Genetics
Background:
- Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with limited treatment options and poor prognosis.
- Current mainstream AML therapies have seen minimal advancement over several decades, necessitating novel therapeutic strategies.
Purpose of the Study:
- To identify novel genetic vulnerabilities and potential therapeutic targets in acute myeloid leukemia (AML).
- To optimize a genome-wide CRISPR screening platform for identifying AML-specific essential genes.
Main Methods:
- Utilized an optimized genome-wide CRISPR screening platform to identify genetic vulnerabilities in AML cells.
- Validated selected gene targets, including KAT2A, through genetic and pharmacological inhibition in AML models.
- Assessed the efficacy of KAT2A inhibition on AML cell growth, differentiation, and apoptosis, and its effect on normal hematopoietic stem and progenitor cells.
Main Results:
- Identified 492 AML-specific cell-essential genes, including known targets like DOT1L, BCL2, and MEN1, and novel clinically actionable candidates.
- KAT2A inhibition demonstrated significant anti-AML activity, inducing myeloid differentiation and apoptosis.
- KAT2A inhibition effectively suppressed the growth of diverse primary human AML genotypes while exhibiting minimal toxicity to normal hematopoietic stem-progenitor cells.
Conclusions:
- KAT2A inhibition represents a promising therapeutic strategy for acute myeloid leukemia (AML).
- The study provides a comprehensive list of genetic vulnerabilities in AML that warrant further investigation for drug development.
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