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Myelodysplastic syndrome

Mutation-specific signaling profiles and kinase inhibitor sensitivities of juvenile myelomonocytic leukemia revealed by induced pluripotent stem cells


Juvenile myelomonocytic leukemia (JMML) is an uncommon myeloproliferative neoplasm driven by Ras pathway mutations and hyperactive Ras/MAPK signaling. Outcomes for many children with JMML remain dismal with current standard-of-care cytoreductive chemotherapy and hematopoietic stem cell transplantation. We used patient-derived induced pluripotent stem cells (iPSCs) to characterize the signaling profiles and potential therapeutic vulnerabilities of PTPN11-mutant and CBL-mutant JMML. We assessed whether MEK, JAK, and PI3K/mTOR kinase inhibitors (i) could inhibit myeloproliferation and aberrant signaling in iPSC-derived hematopoietic progenitors with PTPN11 E76K or CBL Y371H mutations. We detected constitutive Ras/MAPK and PI3K/mTOR signaling in PTPN11 and CBL iPSC-derived myeloid cells. Activated signaling and growth of PTPN11 iPSCs were preferentially inhibited in vitro by the MEKi PD0325901 and trametinib. Conversely, JAK/STAT signaling was selectively activated in CBL iPSCs and abrogated by the JAKi momelotinib and ruxolitinib. The PI3Kδi idelalisib and mTORi rapamycin inhibited signaling and myeloproliferation in both PTPN11 and CBL iPSCs. These findings demonstrate differential sensitivity of PTPN11 iPSCs to MEKi and of CBL iPSCs to JAKi, but similar sensitivity to PI3Ki and mTORi. Clinical investigation of mutation-specific kinase inhibitor therapies in children with JMML may be warranted.

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We thank the human pluripotent stem cell core at the Children’s Hospital of Philadelphia for technical assistance. This work was supported by the National Institutes of Health/National Cancer Institute K08CA184418 (SKT), National Institute of Diabetes and Digestive and Kidney Diseases 5P30DK090969 (MJW) and R01DK100854 (STC), National Heart Lung Blood Institute T32HL0007150 (JAC) and 5RC2HL101606 (MJW), the Leukemia Lymphoma Society 6466-15 (MLL), and Hyundai Hope on Wheels (MLL). MLL is the Benioff Chair of Children’s Health at the University of California, San Francisco and the Deborah and Arthur Ablin Endowed Chair of Pediatric Molecular Oncology. MJW is the Arthur Nienhuis Endowed Chair in Hematology at St Jude Children’s Research Hospital.

Author contributions

SKT designed and directed the study, performed experiments, analyzed data, and wrote the manuscript. JAC designed the study, performed experiments, and analyzed data. SG-B, DP, ALG, and GL performed experiments and analyzed data. MLL provided critical clinical specimens. MLW contributed to study design and oversight. STC and DLF designed and directed the study, analyzed data, and edited the manuscript. All authors reviewed the final version of the manuscript.

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Correspondence to Sarah K. Tasian.

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Conflict of interest

SKT receives research funding from Gilead Sciences for unrelated studies. SKT and MLL receive research funding from the Incyte Corporation for unrelated studies.

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