Among patients with AF10-rearranged acute myeloid leukemia (AML), JAK1 inhibition appears to be a promising therapeutic target, according to the results of a mouse model published in Blood.
The AF10/MLLT10 gene has previously been implicated in chromosomal translocations in multiple leukemias, including AML. AF10/MLLT10 is linked with production of the AF10 fusion protein, which is linked with poor clinical outcomes.
There are, however, no treatments that explicitly target AF10-rearranged disease, representing a significant gap in clinical options; AF10 fusion proteins have, for example, previously been linked with first-line treatment failure in pediatric patients with AML.
For this mouse model, researchers attempted to evaluate for any link between AF10 fusion proteins and JAK/STAT-mediated inflammatory signaling for leukemogenesis, and further to determine whether inhibition of such signaling may represent a possible clinical target in this disease setting.
The authors initially characterized AF10-rearranged AML using transcriptomic, epigenomic, proteomic, and functional genomic tools, and created mouse models of disease driven by common AF10 fusion proteins, including PICALM/CALM-AF10 and KMT2A/MLL-AF10.
The results suggested that AF10 fusion proteins are linked with recruitment of the JAK1 kinase and JAK/STAT-mediated signaling. When the researchers inhibited JAK/STAT signaling by JAK1 deletion or direct JAK and STAT3 inhibition with itacitinib and atovaquone, respectively, anti-cancer effects were noted in both murine and human cell line models.
“A clinical trial is currently ongoing for atovaquone combined with chemotherapy in de novo AML (ClinicalTrials.gov identifier NCT03568994),” the authors wrote. “Our studies showing potent effects of atovaquone in mouse and human AF10-[rearranged] leukemia cells indicate a novel therapeutic approach in this disease in addition to currently used therapies.”
Disclosure: The study author(s) declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Chen BR, Deshpande A, Barbosa K, et al. A JAK/STAT-mediated inflammatory signaling cascade drives oncogenesis in AF10-rearranged AML. Blood. 2021;137(24):3403-15. doi:10.1182/blood.2020009023