Resistance to mitochondrial apoptosis predicts inferior treatment outcomes in patients with diverse tumor types, including T-cell acute lymphoblastic leukemia (T-ALL). However, the genetic basis for variability in this mitochondrial apoptotic phenotype is poorly understood, preventing its rational therapeutic targeting. Using BH3 profiling and exon sequencing analysis of childhood T-ALL clinical specimens, we found that mitochondrial apoptosis resistance was most strongly associated with activating mutations of JAK3. Mutant JAK3 directly repressed apoptosis in leukemia cells, because its inhibition with mechanistically distinct pharmacologic inhibitors resulted in reversal of mitochondrial apoptotic blockade. Inhibition of JAK3 led to loss of MEK, ERK and BCL2 phosphorylation, and BH3 profiling revealed that JAK3-mutant primary T-ALL patient samples were characterized by a dependence on BCL2. Treatment of JAK3-mutant T-ALL cells with the JAK3 inhibitor tofacitinib in combination with a spectrum of conventional chemotherapeutics revealed synergy with glucocorticoids, in vitro and in vivo. These findings thus provide key insights into the molecular genetics of mitochondrial apoptosis resistance in childhood T-ALL, and a compelling rationale for a clinical trial of JAK3 inhibitors in combination with glucocorticoids for patients with JAK3-mutant T-ALL.
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We are grateful to the patients and families who provided samples for these studies. This work was supported by the V Foundation for Cancer Research, NIH R01 CA193651, and the Boston Children’s Hospital Translational Research Program. The Children’s Oncology Group work was supported by U10 CA98543 (COG Chair’s grant), U10 CA98413 (COG Statistical Center), U24 CA114766 (COG Specimen Banking), U10 CA 180886 (COG Operations Center), and U10 CA 180899 (COG Statistics and Data Center). SPH is the Jeffrey E. Perelman Distinguished Chair in the Department of Pediatrics, Children’s Hospital of Philadelphia. AG is the Louis K. Diamond Chair in Pediatric Hematology/Oncology at Boston Children’s Hospital.
SPH has received consulting fees from Novartis, honoraria from Amgen, Jazz Pharmaceuticals and Servier, and owns common stock in Amgen. LBS has received research funding from Novartis. DTT has served on advisory boards for BEAM Therapeutics, Janssen, and Sobi and receives research funding from Neoimmune Tech and BEAM Therapeutics. AL receives research support from AbbVie, AstraZeneca and Novartis, and is a cofounder and equity holder in Flash Therapeutics and Vivid Bioscience. AG receives research support from Astellas Pharma and is on an advisory board of Attivare Therapeutics. The authors have no other relevant conflicts of interest to disclose.
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Bodaar, K., Yamagata, N., Barthe, A. et al. JAK3 mutations and mitochondrial apoptosis resistance in T-cell acute lymphoblastic leukemia. Leukemia 36, 1499–1507 (2022). https://doi.org/10.1038/s41375-022-01558-5