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ACUTE LYMPHOBLASTIC LEUKEMIA

JAK3 mutations and mitochondrial apoptosis resistance in T-cell acute lymphoblastic leukemia

Leukemia volume 36, pages 1499–1507 (2022)Cite this article

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Abstract

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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Fig. 1: JAK3 mutations are associated with resistance to mitochondrial apoptosis in human T-ALL.
Fig. 2: JAK3-activating mutations repress mitochondrial apoptosis in T-ALL.
Fig. 3: JAK3 positively regulates phosphorylation of MEK, ERK and BCL2, and JAK3-mutant primary T-ALLs are characterized by BCL2 dependence.
Fig. 4: Tofacitinib treatment synergizes with corticosteroids.
Fig. 5: In vivo activity of the combination of tofacitinib and dexamethasone in human JAK3-mutant T-ALL.

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Acknowledgements

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.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, 02115, USA

    Kimberly Bodaar, Natsuko Yamagata, Anais Barthe, Jack Landrigan, Melissa Burns, Lewis B. Silverman & Alejandro Gutierrez

  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA

    Triona Ni Chonghaile & Anthony Letai

  3. Deparment of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland

    Triona Ni Chonghaile

  4. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA

    Melissa Burns, Lewis B. Silverman & Alejandro Gutierrez

  5. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA

    Kristen E. Stevenson

  6. Department of Global Pediatric Medicine, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Meenakshi Devidas

  7. Ben Towne Center for Childhood Cancer Research, Seattle Children’s Research Institute, and the Department of Pediatrics, Seattle Children’s Hospital, University of Washington, Seattle, WA, 98105, USA

    Mignon L. Loh

  8. Division of Oncology and the Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA

    Stephen P. Hunger & David T. Teachey

  9. Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, 90027, USA

    Brent Wood

  10. Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands

    Jules P. Meijerink

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  1. Kimberly Bodaar
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Contributions

KB and AG conceived the project. KB, NY, AB, JL, TNC, and MB designed and performed experiments and interpreted data. KES and MD performed statistical analyses and interpreted data. MLL, SPH, BW, LBS, DTT, JPM, and AL aided in data collection of primary patient samples, and in analysis and interpretation of data. KB, NY, and AG wrote the paper with input from all co-authors.

Corresponding author

Correspondence to Alejandro Gutierrez.

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Competing interests

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

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