JAKed up phenotype of CEBPA-mutant AML.

The landscape of recurrent genetic events in AML has been elegantly unraveled in recent years; however, for most disease subsets this has not yet led to facile deployment of therapeutics targeting aberrant genetic events. The resulting gap in our ability to decipher genetic drivers versus our capacity to harness this knowledge for therapeutic advantage will require the integration of genotype information with transcriptomic, proteomic, and drug response data. The studies by Lavallée et al and Maxson et al conclude that AML patients with biallelic mutation of CCAAT/enhancer binding protein a (CEBPA) exhibit dysregulation of and dependence upon Janus kinase–signal transducer and activator of transcription (JAK-STAT) signaling. In the first study, Lavallée et al show that JAK-STAT pathways are dysregulated more frequently than average in biallelic CEBPA (CEBPA)–mutated AML, which correlates with sensitivity to JAK kinase inhibitors. Both this study by Lavallée et al and another study by Maxson et al show that CEBPA mutations also frequently coincide with secondary mutations in JAK-STAT pathway regulators, especially granulocyte colony-stimulating factor 3 receptor (CSF3R). These findings yield the exciting conclusion that JAK kinase inhibitors could be an effective component of improved therapeutic regimens for AML patients with CEBPA mutation, a hypothesis that can be testedwith prospective clinical trials targeted to this patient population. CEBPA is a transcription factor that is crucial for regulating myeloid lineage development. In particular, it has been shown to regulate expression of CSF3R, thereby promoting neutrophil differentiation. Mutations in CEBPA are observed in 5% to 15% of AML patients, and those mutations can be classified into the following 3 categories: (1) monoallelic mutation, (2) typical CEBPA AML (ie, biallelic mutation with one allele harboring an N-terminal frameshift or nonsense mutation and the other allele having an inframe insertion or deletion of the C terminus), and (3) atypical CEBPA AML (ie, biallelic mutation with other configurations of mutations on each allele [eg, point mutations, two N-terminal mutations]). Prior studies have shown that CEBPA AML patients exhibit distinct gene expression patterns compared with those who have wild-type (WT) or monoallelic CEBPA AML, and only CEBPA mutation confers improved prognosis. However, the significance of these CEBPA AML gene expression signatures for disease pathogenesis or design of targeted therapies has remained unclear. CSF3R is a cell surface receptor that binds the ligand CSF3 and activates downstream signaling cascades, most notably JAK-STAT Uniform JAK inhibitor sensitivity enriched for CSF3RT618I Biallelic CEBPA variants: N-terminal fs/non-sense C-terminal in-frame in/del Biallelic CEBPA variants: Other configuration of variants Gene expression similar to typical Biallelic CEBPA variants: Other configuration of variants Gene expression not similar to typical Wild-type or monoallelic CEBPA variants CEBPAbi (typical) CEBPAbi (atypical) GEP+ CEBPAbi (atypical) GEP– CEBPAmonoallelic CEBPAWT