Checkmate to CHK1 in T-cell ALL?

DNA replication ensures accurate duplication of the original genetic information present in a cell in order for it to be properly transmitted to daughter cells. However, replication can be perturbed, for instance in rapidly dividing cancer cells, in a process referred to as replication stress (RS). Checkpoint kinase 1 (CHK1) is an essential component of the ATR-dependent DNA damage-response pathway that protect cells from RS by preventing replication fork collapse and activating homologous DNA repair. The ATR-CHK1 pathway is triggered upon exposure of single-stranded DNA that arises with the stalling of replication forks [1], and it is required to reset proper origin firing, and to promote fork stability and checkpoint activation, delaying mitosis until replication is completed and thereby avoiding mitotic catastrophe [2]. Whereas these functions point towards a tumor suppressor role for CHK1, mouse models modulating ATR-CHK1 expression and genetic evidence from human tumors suggest otherwise: Atr and Chk1 knockout models do not display higher tumor frequency; Chk1 favors oncogene-induced transformation in mice; CHK1 is frequently overexpressed in human cancers, while loss-of-function mutations are rare [2, 3]. Moreover, CHK1 affords protection against DNA damaging agents, a fact that prompted the use of CHK1 inhibitors as chemosensitizers [4]. Similarly, tumors whose oncogenic profile fuels RS were proposed to become addicted to ATR-CHK1 response [1, 2]. In our recent study published in Oncogene [5], we hypothesized that T-cell acute lymphoblastic leukemia (TALL), an aggressive hematological cancer arising from T-cell precursor clonal expansion, could be one of such tumors and showed that CHK1 plays a key role in TALL cell maintenance. TALL cells tend to be highly proliferative due to a myriad of genetic lesions that culminate in cyclin-dependent kinase hyperactivation, and deregulated progression of S-phase that may impact on DNA replication [5, 6]. We found that TALL cells overexpressed CHK1 mRNA and protein as compared to normal hematopoietic progenitors. This was accompanied by aberrantly high CHK1 kinase activity, likely triggered by high basal levels of RS [5]. Experimental inactivation of CHK1, by a CHK1 selective inhibitor (PF-00477736) or by gene silencing, demonstrated that CHK1 is essential to control the accumulation of RS and to prevent apoptosis of TALL cells that appear to enter mitosis without having concluded DNA replication. Furthermore, accumulation of DNA damage in the context of CHK1 loss induced the activation of the ATM-CHK2 DNA double-strand break (DSB) response pathway, likely due to DSB formation upon the collapse of …