The molecular dissection of the landscape of AML has been at the leading edge of cancer discovery, but the treatment of AML has remained largely unchanged. A defining feature of AML is a differentiation defect, yet current therapy focuses almost exclusively on cytotoxic chemotherapy. In this issue, Järås et al. report that Csnk1a1 inhibition induces differentiation in AML and is selectively essential for AML survival in vivo. Because Csnk1a1 is a druggable target, this work identifies a propitious new strategy for the treatment of AML and also demonstrates the value of re-mining existing data sets.
In today’s era of moderate-cost screening, scientific inquiry frequently begins with the generation of new screening data. A time-saving and highly cost-effective approach, however, is to re-mine already existing data sets. In a previous 2013 study, Miller et al. performed a pooled in vivo shRNA screen in primary MLL-AF9–rearranged mouse AML to identify candidate therapeutic targets. In the current study, this data was re-mined and a top scoring serine threonine kinase, Csnk1a1, prioritized. The authors demonstrated that Csnk1a1 is essential for AML cell survival in vivo, but not for the survival of normal hematopoietic stem and progenitor cells, suggesting a therapeutic window for the targeting of Csnk1a1 in patients with AML.
The next step was to elucidate the mechanistic role of Csnk1a1 in AML, a critical but challenging step. Using state-of-the-art functional genomics (a targeted pooled in vivo shRNA screen) and expression profiling tools, the authors found that the inhibition of Csnk1a1 reduced Rps6 phosphorylation in AML cells, induced p53 expression, and triggered a myeloid differentiation program. Importantly, Tp53-null leukemia did not respond to knockdown nor to a small molecule inhibitor of Csnk1a1, strongly supporting the mechanistic importance of the p53 expression program to the response to Csnk1a1 inhibition. These findings raise the intriguing possibility that Csnk1a1 inhibition might represent a more generalizable treatment strategy to induce the p53 program in other Tp53 wild-type cancers.
These results both illuminate the power of functional genomics in therapeutic target identification and are specifically a breakthrough in the identification of novel approaches to differentiation therapy for AML. In light of the strong therapeutic window for targeting Csnk1a1 in leukemic versus normal cells, the relative ease of drugging kinases, and the promise of differentiation treatment strategies, this study supports the medicinal development of Csnk1a1 small molecule inhibitors as an exciting potential therapeutic opportunity for patients with AML.