Posted: Tuesday, June 8, 2021
Leukemias harboring AF10/MLLT10 gene fusions are associated with a poor prognosis. Aniruddha Deshpande, PhD, of the Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, and colleagues identified JAK inhibitors and the STAT3 inhibitor, antimicrobial atovaquone as potential drug candidates for the treatment of pediatric patients with AF10-rearranged acute myeloid leukemia (AML). Their findings were published in the journal Blood.
“While highly successful therapies have been found for other blood cancers, most children diagnosed with this AML subtype are still treated with harsh, toxic chemotherapies,” commented Dr. Deshpande in an institutional press release. “We are excited about this study because we uncovered two promising therapeutic targets for which drugs already exist, setting the stage for potential clinical trials."
The investigators conducted experiments using mice, cell culture, and several assays using transcriptomic, epigenomic, proteomic, and functional genomic approaches to examine the mechanisms underlying AF10 fusion–positive leukemogenesis. In addition, inducible mouse models were generated using the most common AF10 fusion proteins: PICALM/CALM-AF10 and KMT2A/MLL-AF10.
A detailed map was created to outline the gene networks and protein interactors that seem to be associated with the key AF10 fusions involved in leukemia. Specifically, the investigators noted that AF10 fusions activate a cascade of JAK/STAT-mediated inflammatory signaling through the direct recruitment of JAK1 kinase. In mouse and human models of AF10 fusion–positive AML, potent antioncogenic effects were elicited by inhibiting the JAK/STAT signaling by genetic JAK1 deletion or through pharmacologic JAK/STAT inhibition. Of note, treatment with atovaquone seemed to shrink AML tumors and extend survival in mice with the CALM-AF10 mutation.
Disclosure: For full disclosures of the study authors, visit ashpublications.org.