Abstract:
:Acute myeloid leukemia (AML) is a heterogeneous disease with complex molecular pathophysiology. To systematically characterize AML's genetic dependencies, we conducted genome-scale short hairpin RNA screens in 17 AML cell lines and analyzed dependencies relative to parallel screens in 199 cell lines of other cancer types. We identified 353 genes specifically required for AML cell proliferation. To validate the in vivo relevance of genetic dependencies observed in human cell lines, we performed a secondary screen in a syngeneic murine AML model driven by the MLL-AF9 oncogenic fusion protein. Integrating the results of these interference RNA screens and additional gene expression data, we identified the transcription factor ZEB2 as a novel AML dependency. ZEB2 depletion impaired the proliferation of both human and mouse AML cells and resulted in aberrant differentiation of human AML cells. Mechanistically, we showed that ZEB2 transcriptionally represses genes that regulate myeloid differentiation, including genes involved in cell adhesion and migration. In addition, we found that epigenetic silencing of the miR-200 family microRNAs affects ZEB2 expression. Our results extend the role of ZEB2 beyond regulating epithelial-mesenchymal transition (EMT) and establish ZEB2 as a novel regulator of AML proliferation and differentiation.
journal_name
Bloodjournal_title
Bloodauthors
Li H,Mar BG,Zhang H,Puram RV,Vazquez F,Weir BA,Hahn WC,Ebert B,Pellman Ddoi
10.1182/blood-2016-05-714493subject
Has Abstractpub_date
2017-01-26 00:00:00pages
497-508issue
4eissn
0006-4971issn
1528-0020pii
blood-2016-05-714493journal_volume
129pub_type
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