Abstract
Checkpoint kinase 1 (CHK1) is critical for intrinsic cell cycle control and coordination of cell cycle progression in response to DNA damage. Despite its essential function, CHK1 has been identified as a target to kill cancer cells and studies using Chk1 haploinsufficient mice initially suggested a role as tumor suppressor. Here, we report on the key role of CHK1 in normal B-cell development, lymphomagenesis and cell survival. Chemical CHK1 inhibition induces BCL2-regulated apoptosis in primary as well as malignant B-cells and CHK1 expression levels control the timing of lymphomagenesis in mice. Moreover, total ablation of Chk1 in B-cells arrests their development at the pro-B cell stage, a block that, surprisingly, cannot be overcome by inhibition of mitochondrial apoptosis, as cell cycle arrest is initiated as an alternative fate to limit the spread of damaged DNA. Our findings define CHK1 as essential in B-cell development and potent target to treat blood cancer.
Highlights
Checkpoint kinase 1 (CHK1) is critical for intrinsic cell cycle control and coordination of cell cycle progression in response to DNA damage
We chose to interrogate a number of Burkitt lymphoma cell lines, assessed their CHK1 expression and activity levels (Fig. 1a) and treated them with the selective CHK1 inhibitors (CHKi), PF-477736 or CHIR-124 to assess their susceptibility to and mode of cell death
As most anticancer drugs trigger intrinsic apoptosis, we monitored the consequences of BCL2 overexpression in 5/10 cell lines and observed that, similar to caspase inhibition, this potently protected cells from death induced by CHK1i (Fig. 1d, Supplementary Fig. 1D)
Summary
Checkpoint kinase 1 (CHK1) is critical for intrinsic cell cycle control and coordination of cell cycle progression in response to DNA damage. Burkitt lymphoma, a MYC-driven malignancy of germinal center B cells, shows highest mRNA levels across all cancers in the TGCA database, suggesting that high CHK1 activity might be needed to balance replication stress caused by deregulated MYC, or other oncogenic events that drive extensive proliferation[30] In line with this hypothesis, Eμ-MYCdriven murine lymphomas are highly responsive to CHK1 inhibitors in transplant models and several human blood cancer cell lines, including Burkitt and Diffuse large B cell lymphomas (DLBCL) respond well to CHK1 inhibition alone or when combined with antimetabolites or ATR inhibitors[31,32,33,34]. A second study showed impressive efficacy of an ATR inhibitor, targeting the same vulnerability, as single agent in MLL-rearranged AML36
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