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Published on: September 1, 2019
CHK1-S, a splicing variant of CHK1, suppresses chronic myeloid leukemia
Hu Lei1, Hanzhang Xu1, Yingying Wang1
1Institute for Translational Medicine on Cell Fate and Disease, Shanghai Ninth People's Hospital, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Abstract:
Checkpoint kinase 1 (CHK1) is a crucial protein involved in the cell cycle checkpoint during the DNA damage response and is essential for sustaining leukemia cell activity. CHK1-S (excluded exon 3) is an alternative splice variant of CHK1. Here, we demonstrate that CHK1-S is highly expressed in wild-type mouse bone marrow, and the ratio of CHK1-S to CHK1 is significantly higher compared to other tissues. The BCR-ABL protein reduces the expression of CHK1-S while increasing CHK1 levels in vitro and in vivo. Furthermore, the expression of CHK1-S is significantly reduced in the bone marrow mononuclear cells of newly diagnosed chronic myeloid leukemia (CML) patients. Inhibition of BCR-ABL activity with imatinib or knockdown of BCR-ABL can restore the expression of CHK1-S in K562 cells. Additionally, restoring CHK1-S can inhibit the proliferation of K562 cells and increase the proportion of cells in the G2/M phase. Mechanistically, the splicing factors transformer 2α (TRA2A) and TRA2B are associated with the selective splicing of CHK1-S in K562 cells. Our findings demonstrate that CHK1-S functions in opposition to CHK1, acting as a suppressor of CML.
Insights
Checkpoint kinase 1-S (CHK1-S) suppresses chronic myeloid leukemia (CML) by opposing CHK1 activity. Reduced CHK1-S in CML patients highlights its role as a tumor suppressor.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Checkpoint kinase 1 (CHK1) is vital for DNA damage response and leukemia cell survival.
- CHK1-S is an alternative splice variant of CHK1, found highly in mouse bone marrow.
Purpose of the Study:
- To investigate the role of CHK1-S in chronic myeloid leukemia (CML).
- To understand the regulatory mechanism of CHK1-S expression by BCR-ABL.
- To explore the therapeutic potential of CHK1-S in CML.
Main Methods:
- Quantitative analysis of CHK1 and CHK1-S expression in mouse and human samples.
- In vitro and in vivo experiments involving BCR-ABL inhibition and knockdown.
- Cell proliferation assays and cell cycle analysis (G2/M phase).
- Investigation of splicing factors TRA2A and TRA2B involvement.
Main Results:
- CHK1-S is highly expressed in wild-type mouse bone marrow, with a higher ratio to CHK1 compared to other tissues.
- BCR-ABL reduces CHK1-S expression while increasing CHK1 levels.
- CHK1-S expression is significantly decreased in newly diagnosed CML patients.
- Imatinib treatment or BCR-ABL knockdown restores CHK1-S expression in K562 cells.
- Restoring CHK1-S inhibits K562 cell proliferation and increases G2/M phase cells.
- TRA2A and TRA2B are involved in CHK1-S splicing.
Conclusions:
- CHK1-S acts as a tumor suppressor in CML, opposing CHK1 function.
- Dysregulation of CHK1-S by BCR-ABL contributes to CML pathogenesis.
- Restoring CHK1-S expression may offer a novel therapeutic strategy for CML.
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