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.

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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 ( 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