Abstract
Histiocytoses are inflammatory myeloid neoplasms often driven by somatic activating mutations in mitogen-activated protein kinase (MAPK) cascade genes. H syndrome is an inflammatory genetic disorder caused by germ line loss-of-function mutations in SLC29A3, encoding the lysosomal equilibrative nucleoside transporter 3 (ENT3). Patients with H syndrome are predisposed to develop histiocytosis, yet the mechanism is unclear. Here, through phenotypic, molecular, and functional analysis of primary cells from a cohort of patients with H syndrome, we reveal the molecular pathway leading to histiocytosis and inflammation in this genetic disorder. We show that loss of function of ENT3 activates nucleoside-sensing toll-like receptors (TLR) and downstream MAPK signaling, inducing cytokine secretion and inflammation. Importantly, MEK inhibitor therapy led to resolution of histiocytosis and inflammation in a patient with H syndrome. These results demonstrate a yet-unrecognized link between a defect in a lysosomal transporter and pathological activation of MAPK signaling, establishing a novel pathway leading to histiocytosis and inflammation.
| Original language | American English |
|---|---|
| Journal | Blood |
| DOIs | |
| State | Accepted/In press - 2023 |
Bibliographical note
Funding Information:S.I. and S.E. are supported by the Israel Cancer Association, the Chaim Association, the Israel Childhood Cancer Fund (New York, NY), and the Israeli Ministry of Health . S.I. is an Israel Childhood Cancer Fund grant recipient and the Giorgio and Dora Shapiro Professor of Hematological Malignancies. Further support was obtained from the Israel Science Foundation Israel Precision Medicine Partnership grant, Waxman Cancer Research Foundation (New York, NY), the Noaber Foundation (Tel Aviv, Israel), and the Department of Systems Biology at City of Hope (Duarte, CA). S.Y. is supported by the Israel Science Foundation . S.E. is supported by the Davidoff Foundation . M.Z. and J.T. are supported by the National Institute for Cancer Research (Program EXCELES, ID project number LX22NPO5102), funded by the European Union (EU), Next Generation EU . R.L. is supported by an Ariane de Rothschild doctoral studentship .
Funding Information:
The authors thank the patients and their families for participating in this study. The authors thank Eviatar Weizmann from the Mantoux Bioinformatics institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, for the bioinformatic analysis of single-cell RNA sequencing data; and Abed Nasereddin and Idit Shiff from the Core Research Facility of Hebrew University, Ein Karem Campus, for the preparation and sequencing of 10X libraries. The authors thank Jean-Francois Emile from Universite de Versailles Saint-Quentin, Paris, France, for the histopathological revision of our patient's tumor; and Naomi Litichever and Dina Kugel, data managers at the Department of Pediatric Hematology and Oncology, Schneider Children's Medical Center of Israel. Furthermore, the authors thank Tamar Natanzon-Bracha, Rina Baslo, and all the nurses at the Schneider Medical Center Pediatric Hematology-Oncology Day Center for their assistance with blood sample collection; and Oren Parnas, Abraham Zlotogorski, Vered Molho-Pessach, and Eli Pikarsky for useful discussions. S.I. and S.E. are supported by the Israel Cancer Association, the Chaim Association, the Israel Childhood Cancer Fund (New York, NY), and the Israeli Ministry of Health. S.I. is an Israel Childhood Cancer Fund grant recipient and the Giorgio and Dora Shapiro Professor of Hematological Malignancies. Further support was obtained from the Israel Science Foundation Israel Precision Medicine Partnership grant, Waxman Cancer Research Foundation (New York, NY), the Noaber Foundation (Tel Aviv, Israel), and the Department of Systems Biology at City of Hope (Duarte, CA). S.Y. is supported by the Israel Science Foundation. S.E. is supported by the Davidoff Foundation. M.Z. and J.T. are supported by the National Institute for Cancer Research (Program EXCELES, ID project number LX22NPO5102), funded by the European Union (EU), Next Generation EU. R.L. is supported by an Ariane de Rothschild doctoral studentship. Contribution: R.S. S.I. and S.E. designed the study; R.S. S.Y. S.I. and S.E. analyzed and interpreted the data; R.S. performed most experiments; S.Y. R.L. and I.H. designed, performed, and analyzed Cytek flow cytometry experiments; O.D. G.A. Y. Birger, D.B. A.B. L.H. E.K. G.L. S.S. N.S.A. and S.E. were involved in patient care; O.D. E.K. and S.E. collected patient data and samples; E.O. and D.K. analyzed histopathology data; M.S.R. evaluated radiographic studies; M.Z. and J.T. performed and analyzed whole-transcriptome sequencing; S.C.-K. provided technical assistance; I.G. and Y. Borovitz critically reviewed the experiments and provided important advice; R.S. S.I. S.Y. and S.E. wrote the manuscript; and all authors approved the final version of the manuscript.
Publisher Copyright:
© 2023 The American Society of Hematology