Targeting of apoptosis gene loci by reprogramming factors leads to selective eradication of leukemia cells

Yajie Wang, Ting Lu, Guohuan Sun, Yawei Zheng, Shangda Yang, Hongyan Zhang, Sha Hao, Yanfeng Liu, Shihui Ma, Houyu Zhang, Yongxin Ru, Shaorong Gao, Kuangyu Yen (), Hui Cheng () and Tao Cheng ()
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Yajie Wang: State Key Laboratory of Experimental Hematology
Ting Lu: School of Basic Medical Sciences, Southern Medical University
Guohuan Sun: State Key Laboratory of Experimental Hematology
Yawei Zheng: State Key Laboratory of Experimental Hematology
Shangda Yang: State Key Laboratory of Experimental Hematology
Hongyan Zhang: State Key Laboratory of Experimental Hematology
Sha Hao: State Key Laboratory of Experimental Hematology
Yanfeng Liu: State Key Laboratory of Experimental Hematology
Shihui Ma: State Key Laboratory of Experimental Hematology
Houyu Zhang: School of Basic Medical Sciences, Southern Medical University
Yongxin Ru: State Key Laboratory of Experimental Hematology
Shaorong Gao: Tongji University
Kuangyu Yen: School of Basic Medical Sciences, Southern Medical University
Hui Cheng: State Key Laboratory of Experimental Hematology
Tao Cheng: State Key Laboratory of Experimental Hematology

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract Applying somatic cell reprogramming strategies in cancer cell biology is a powerful approach to analyze mechanisms of malignancy and develop new therapeutics. Here, we test whether leukemia cells can be reprogrammed in vivo using the canonical reprogramming transcription factors-Oct4, Sox2, Klf4, and c-Myc (termed as OSKM). Unexpectedly, we discover that OSKM can eradicate leukemia cells and dramatically improve survival of leukemia-bearing mice. By contrast, OSKM minimally impact normal hematopoietic cells. Using ATAC-seq, we find OSKM induce chromatin accessibility near genes encoding apoptotic regulators in leukemia cells. Moreover, this selective effect also involves downregulation of H3K9me3 as an early event. Dissection of the functional effects of OSKM shows that Klf4 and Sox2 play dominant roles compared to c-Myc and Oct4 in elimination of leukemia cells. These results reveal an intriguing paradigm by which OSKM-initiated reprogramming induction can be leveraged and diverged to develop novel anti-cancer strategies.

Date: 2019
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DOI: 10.1038/s41467-019-13411-y

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