Loss of function of ENT3 drives histiocytosis and inflammation through TLR-MAPK signaling

Ruth Shiloh; Ruth Lubin; Odeya David; Ifat Geron; Elimelech Okon; Idit Hazan; Marketa Zaliova; Gil Amarilyo; Yehudit Birger; Yael Borovitz; Dafna Brik; Arnon Broides; Sarit Cohen-Kedar; Liora Harel; Eyal Kristal; Daria Kozlova; Galina Ling; Mika Shapira Rootman; Noa Shefer Averbuch; Shiri Spielman; Jan Trka; Shai Izraeli; Simon Yona; Sarah Elitzur

doi:10.1182/blood.2023020714

Loss of function of ENT3 drives histiocytosis and inflammation through TLR-MAPK signaling

Ruth Shiloh^*, Ruth Lubin, Odeya David, Ifat Geron, Elimelech Okon, Idit Hazan, Marketa Zaliova, Gil Amarilyo, Yehudit Birger, Yael Borovitz, Dafna Brik, Arnon Broides, Sarit Cohen-Kedar, Liora Harel, Eyal Kristal, Daria Kozlova, Galina Ling, Mika Shapira Rootman, Noa Shefer Averbuch, Shiri SpielmanJan Trka, Shai Izraeli, Simon Yona, Sarah Elitzur^*

^*Corresponding author for this work

Institute of Biomedical Research at the Faculty of Dental Medicine

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

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	English
Pages (from-to)	1740-1751
Number of pages	12
Journal	Blood
Volume	142
Issue number	20
DOIs	https://doi.org/10.1182/blood.2023020714
State	Published - 16 Nov 2023

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Publisher Copyright:
© 2023 The American Society of Hematology

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Shiloh, R., Lubin, R., David, O., Geron, I., Okon, E., Hazan, I., Zaliova, M., Amarilyo, G., Birger, Y., Borovitz, Y., Brik, D., Broides, A., Cohen-Kedar, S., Harel, L., Kristal, E., Kozlova, D., Ling, G., Shapira Rootman, M., Shefer Averbuch, N., ... Elitzur, S. (2023). Loss of function of ENT3 drives histiocytosis and inflammation through TLR-MAPK signaling. Blood, 142(20), 1740-1751. https://doi.org/10.1182/blood.2023020714

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title = "Loss of function of ENT3 drives histiocytosis and inflammation through TLR-MAPK signaling",

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.",

author = "Ruth Shiloh and Ruth Lubin and Odeya David and Ifat Geron and Elimelech Okon and Idit Hazan and Marketa Zaliova and Gil Amarilyo and Yehudit Birger and Yael Borovitz and Dafna Brik and Arnon Broides and Sarit Cohen-Kedar and Liora Harel and Eyal Kristal and Daria Kozlova and Galina Ling and {Shapira Rootman}, Mika and {Shefer Averbuch}, Noa and Shiri Spielman and Jan Trka and Shai Izraeli and Simon Yona and Sarah Elitzur",

note = "Publisher Copyright: {\textcopyright} 2023 The American Society of Hematology",

year = "2023",

month = nov,

day = "16",

doi = "10.1182/blood.2023020714",

language = "אנגלית",

volume = "142",

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Shiloh, R, Lubin, R, David, O, Geron, I, Okon, E, Hazan, I, Zaliova, M, Amarilyo, G, Birger, Y, Borovitz, Y, Brik, D, Broides, A, Cohen-Kedar, S, Harel, L, Kristal, E, Kozlova, D, Ling, G, Shapira Rootman, M, Shefer Averbuch, N, Spielman, S, Trka, J, Izraeli, S, Yona, S & Elitzur, S 2023, 'Loss of function of ENT3 drives histiocytosis and inflammation through TLR-MAPK signaling', Blood, vol. 142, no. 20, pp. 1740-1751. https://doi.org/10.1182/blood.2023020714

TY - JOUR

T1 - Loss of function of ENT3 drives histiocytosis and inflammation through TLR-MAPK signaling

AU - Shiloh, Ruth

AU - Lubin, Ruth

AU - David, Odeya

AU - Geron, Ifat

AU - Okon, Elimelech

AU - Hazan, Idit

AU - Zaliova, Marketa

AU - Amarilyo, Gil

AU - Birger, Yehudit

AU - Borovitz, Yael

AU - Brik, Dafna

AU - Broides, Arnon

AU - Cohen-Kedar, Sarit

AU - Harel, Liora

AU - Kristal, Eyal

AU - Kozlova, Daria

AU - Ling, Galina

AU - Shapira Rootman, Mika

AU - Shefer Averbuch, Noa

AU - Spielman, Shiri

AU - Trka, Jan

AU - Izraeli, Shai

AU - Yona, Simon

AU - Elitzur, Sarah

PY - 2023/11/16

Y1 - 2023/11/16

N2 - 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.

AB - 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.

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U2 - 10.1182/blood.2023020714

DO - 10.1182/blood.2023020714

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C2 - 37738562

AN - SCOPUS:85174215155

SN - 0006-4971

VL - 142

SP - 1740

EP - 1751

JO - Blood

JF - Blood

IS - 20

ER -

Loss of function of ENT3 drives histiocytosis and inflammation through TLR-MAPK signaling

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