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Myelodysplastic syndrome

Fusion driven JMML: a novel CCDC88C–FLT3 fusion responsive to sorafenib identified by RNA sequencing

Leukemia volume 34, pages 662–666 (2020)Cite this article

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Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm of childhood with nearly half of all patients relapsing within 3 years [1, 2]. More than 90% of JMML patients present with initiating mutations in NF1, KRAS, NRAS, RRAS, RRAS2, CBL, and PTPN11, all leading to hyperactivation of the Ras pathway [3]. Patients with additional molecular alterations including cytogenetic abnormalities, and in particular, point mutations in SETBP1 have inferior outcomes [4]. At present, hematopoietic stem cell transplantation (HSCT) is the only curative therapy, with the primary cause of death being relapse or progression to acute myeloid leukemia (AML) [5]. Recently, JMML patients who did not display Ras pathway mutations were found to have ALK and ROS1 fusions that were sensitive to ALK inhibition [6]. Given the poor overall survival of JMML patients even after intensive treatments such as HSCT, opportunities to implement precision medicine should be explored in this disease. Here, we present a JMML patient who failed to respond to conventional cytotoxic chemotherapy and was found to have a novel CCDC88C–FLT3 fusion driving the patient’s leukemia that responded to FLT3 inhibition with sorafenib. Of note, FLT3 fusions and internal tandem duplication (ITD)s give rise to myeloproliferative disorders in mouse models but have yet to be reported in pediatric patients [7].

DNA and RNA were extracted using standard methods from bone marrow, spleen, and peripheral blood mononuclear cells obtained at various time points through the clinical course. Approvals for these studies were obtained from the University of California San Francisco (UCSF) Committee on Human Research. The guardians provided informed consent in accordance with the Declaration of Helsinki.

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Acknowledgements

We thank the family for their willingness to share their story. This work was supported by the National Institutes of Health, National Cancer Institute grant 1U54CA196519 (M.L.L., E.S.); National Institutes of Health, National Heart, Lung, and Blood Institute grant K08HL135434 (E.S.); Alex’s Lemonade Stand, Center of Excellence (M.L.L., E.S.) and the Frank A. Campini Foundation (M.L.L. and E.S.). C.S. is the Damon Runyon-Richard Lumsden Foundation Clinical Investigator supported (in part) by the Damon Runyon Cancer Research Foundation (CI-99-18).

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Authors and Affiliations

  1. Department of Pediatrics, Benioff Children’s Hospital, University of California, San Francisco, San Francisco, CA, USA

    Alexander K. Chao, Julia A. Meyer, Alex G. Lee, Anna Hecht, Ashley K. Koegel, Benjamin S. Braun, E. Alejandro Sweet-Cordero, Christopher C. Dvorak, Mignon L. Loh & Elliot Stieglitz

  2. Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA

    Theodore Tarver & Catherine C. Smith

  3. Department of Pathology, University of California, San Francisco, San Francisco, CA, USA

    Jessica Van Ziffle

  4. Department of Pediatrics, Benioff Children’s Hospital, University of California, San Francisco, Oakland, CA, USA

    Carla Golden

  5. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA

    Benjamin S. Braun, E. Alejandro Sweet-Cordero, Catherine C. Smith, Christopher C. Dvorak, Mignon L. Loh & Elliot Stieglitz

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  1. Alexander K. Chao
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Contributions

A.K.C. and J.A.M. performed the ddPCR and Ba/F3 experiments and analyzed the data; A.G.L. and J.V.Z. analyzed the data; A.K.K., B.S.B., E.A.S., C.C.S., C.C.D., T.T., A.H. all advised on design of the experiments; A.K.C. and E.S. wrote the manuscript; J.A.M., A.G.L., J.V.Z., A.K.K., C.G., B.S.B, E.A.S., C.C.S., C.C.D., M.L.L., T.T., A.H. edited the manuscript; E.S. supervised the experiments; and all authors reviewed the literature, contributed to specific sections, and reviewed the final version of the manuscript.

Corresponding author

Correspondence to Elliot Stieglitz.

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Conflict of interest

C.S. received research funding from FujiFilm and Astellas Pharma. A.K.C. received an honoraria from Bio-Rad for speaking at a symposium. No other authors declare conflicts of interest.

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Chao, A.K., Meyer, J.A., Lee, A.G. et al. Fusion driven JMML: a novel CCDC88C–FLT3 fusion responsive to sorafenib identified by RNA sequencing. Leukemia 34, 662–666 (2020). https://doi.org/10.1038/s41375-019-0549-y

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