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Journal of Hematology & Oncology

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Open Access 01-12-2020 | Imatinib | Research

CRISPR/CAS9-mediated knockout of Abi1 inhibits p185^Bcr-Abl-induced leukemogenesis and signal transduction to ERK and PI3K/Akt pathways

Authors: James Faulkner, Peixin Jiang, Delaney Farris, Ryan Walker, Zonghan Dai

Published in: Journal of Hematology & Oncology | Issue 1/2020

Abstract

Background

Abl interactor 1 (Abi1) is a downstream target of Abl tyrosine kinases and a component of the WAVE regulatory complex (WRC) that plays an important role in regulating actin cytoskeleton remodeling and membrane receptor signaling. While studies using short hairpin RNA (shRNA) have suggested that Abi1 plays a critical role in Bcr-Abl-induced leukemogenesis, the mechanism involved is not clear.

Methods

In this study, we knocked out Abi1 expression in p185^Bcr-Abl-transformed hematopoietic cells using CRISPR/Cas9-mediated gene editing technology. The effects of Abi1 deficiency on actin cytoskeleton remodeling, the Bcr-Abl signaling, IL-3 independent growth, and SDF-induced chemotaxis in these cells were examined by various in vitro assays. The leukemogenic activity of these cells was evaluated by a syngeneic mouse transplantation model.

Results

We show here that Abi1 deficiency reduced the IL3-independent growth and SDF-1α-mediated chemotaxis in p185^Bcr-Abl-transformed hematopoietic cells and inhibited Bcr-Abl-induced abnormal actin remodeling. Depletion of Abi1 also impaired the Bcr-Abl signaling to the ERK and PI3 kinase/Akt pathways. Remarkably, the p185^Bcr-Abl-transformed cells with Abi1 deficiency lost their ability to develop leukemia in syngeneic mice. Even though these cells developed drug tolerance in vitro after prolonged selection with imatinib as their parental cells, the imatinib-tolerant cells remain incapable of leukemogenesis in vivo.

Conclusions

Together, this study highlights an essential role of Abi1 in Bcr-Abl-induced leukemogenesis and provides a model system for dissecting the Abi1 signaling in Bcr-Abl-positive leukemia.

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Title: CRISPR/CAS9-mediated knockout of Abi1 inhibits p185Bcr-Abl-induced leukemogenesis and signal transduction to ERK and PI3K/Akt pathways
Authors: James Faulkner
Peixin Jiang
Delaney Farris
Ryan Walker
Zonghan Dai
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Imatinib
Leukemia
Published in: Journal of Hematology & Oncology / Issue 1/2020
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-020-00867-5

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