Related Experiment Video
Updated: Nov 21, 2025
Evaluation of Abnormal Growth-related Genes of Hematopoietic Stem and Progenitor Cells by Combining CRISPR/Cas9 Technology with Cell Counting
Published on: May 2, 2025
Surface antigen-guided CRISPR screens identify regulators of myeloid leukemia differentiation
Eric Wang1, Hua Zhou2, Bettina Nadorp1
1Department of Pathology and Laura & Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA.
Abstract:
Lack of cellular differentiation is a hallmark of many human cancers, including acute myeloid leukemia (AML). Strategies to overcome such a differentiation blockade are an approach for treating AML. To identify targets for differentiation-based therapies, we applied an integrated cell surface-based CRISPR platform to assess genes involved in maintaining the undifferentiated state of leukemia cells. Here we identify the RNA-binding protein ZFP36L2 as a critical regulator of AML maintenance and differentiation. Mechanistically, ZFP36L2 interacts with the 3' untranslated region of key myeloid maturation genes, including the ZFP36 paralogs, to promote their mRNA degradation and suppress terminal myeloid cell differentiation. Genetic inhibition of ZFP36L2 restores the mRNA stability of these targeted transcripts and ultimately triggers myeloid differentiation in leukemia cells. Epigenome profiling of several individuals with primary AML revealed enhancer modules near ZFP36L2 that associated with distinct AML cell states, establishing a coordinated epigenetic and post-transcriptional mechanism that shapes leukemic differentiation.
Insights
Researchers identified ZFP36L2 as a key regulator in acute myeloid leukemia (AML). Inhibiting this RNA-binding protein promotes cancer cell differentiation, offering a potential new therapy for AML.
Area of Science:
- Molecular Biology
- Cancer Research
- Hematology
Background:
- Cellular differentiation failure is a key characteristic of human cancers, notably acute myeloid leukemia (AML).
- Therapeutic strategies targeting differentiation blockade are crucial for AML treatment.
- Identifying genes that maintain the undifferentiated state of leukemia cells is essential for developing new therapies.
Purpose of the Study:
- To identify novel therapeutic targets for differentiation-based AML treatment.
- To investigate the role of RNA-binding proteins in maintaining leukemia cell undifferentiation.
- To elucidate the molecular mechanisms regulating myeloid cell differentiation in AML.
Main Methods:
- Utilized a cell surface-based CRISPR screening platform to identify genes involved in AML maintenance.
- Investigated the interaction of ZFP36L2 with 3' untranslated regions of myeloid maturation genes.
- Performed epigenome profiling on primary AML samples to analyze enhancer modules associated with ZFP36L2.
Main Results:
- Identified ZFP36L2, an RNA-binding protein, as a critical regulator of AML maintenance and differentiation.
- Demonstrated that ZFP36L2 promotes mRNA degradation of key myeloid maturation genes, thereby suppressing differentiation.
- Showed that genetic inhibition of ZFP36L2 restores mRNA stability and induces myeloid differentiation in leukemia cells.
- Revealed coordinated epigenetic and post-transcriptional regulation of leukemic differentiation involving ZFP36L2.
Conclusions:
- ZFP36L2 is a critical therapeutic target for overcoming differentiation blockade in AML.
- Targeting ZFP36L2 offers a promising strategy for AML treatment by inducing terminal myeloid differentiation.
- Epigenetic and post-transcriptional mechanisms involving ZFP36L2 play a coordinated role in shaping leukemic cell differentiation.
