CHK1-S, a splicing variant of CHK1, suppresses chronic myeloid leukemia.

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.