Granulocyte-derived Resistin Inhibits Monocyte Maturation and Promotes an Immunosuppressive Phenotype in Chronic Myelomonocytic Leukemia Monocytes

Nathan J. Hull; Rachel Cant; Laura A. Guest; Yu-Hung Wang; Kristian Gurashi; Roberto Paredes; Carlos Rivera Rivera; Revekka Lefkati; Hector Huerga Encabo; Chien-Chin Lin; Hwei-Fang Tien; Robert Sellers; Sudhakar Sahoo; Dominique Bonnet; Eric Solary; Dorothee Selimoglu-Buet; Daniel H. Wiseman; Kiran Batta

doi:10.1172/JCI201335

¹Epigenetics of Haematopoiesis Laboratory, Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom

²Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom

³Division of Hematology, National Taiwan University Hospital, Taipei, Taiwan

⁴Computational Biology Support Team, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom

⁵INSERM U1287, Gustave Roussy Cancer Center, Villejuif, France

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¹Epigenetics of Haematopoiesis Laboratory, Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom

²Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom

³Division of Hematology, National Taiwan University Hospital, Taipei, Taiwan

⁴Computational Biology Support Team, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom

⁵INSERM U1287, Gustave Roussy Cancer Center, Villejuif, France

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¹Epigenetics of Haematopoiesis Laboratory, Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom

²Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom

³Division of Hematology, National Taiwan University Hospital, Taipei, Taiwan

⁴Computational Biology Support Team, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom

⁵INSERM U1287, Gustave Roussy Cancer Center, Villejuif, France

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¹Epigenetics of Haematopoiesis Laboratory, Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom

²Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom

³Division of Hematology, National Taiwan University Hospital, Taipei, Taiwan

⁴Computational Biology Support Team, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom

⁵INSERM U1287, Gustave Roussy Cancer Center, Villejuif, France

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¹Epigenetics of Haematopoiesis Laboratory, Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom

²Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom

³Division of Hematology, National Taiwan University Hospital, Taipei, Taiwan

⁴Computational Biology Support Team, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom

⁵INSERM U1287, Gustave Roussy Cancer Center, Villejuif, France

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¹Epigenetics of Haematopoiesis Laboratory, Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom

²Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom

³Division of Hematology, National Taiwan University Hospital, Taipei, Taiwan

⁴Computational Biology Support Team, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom

⁵INSERM U1287, Gustave Roussy Cancer Center, Villejuif, France

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¹Epigenetics of Haematopoiesis Laboratory, Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom

²Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom

³Division of Hematology, National Taiwan University Hospital, Taipei, Taiwan

⁴Computational Biology Support Team, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom

⁵INSERM U1287, Gustave Roussy Cancer Center, Villejuif, France

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¹Epigenetics of Haematopoiesis Laboratory, Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom

²Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom

³Division of Hematology, National Taiwan University Hospital, Taipei, Taiwan

⁴Computational Biology Support Team, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom

⁵INSERM U1287, Gustave Roussy Cancer Center, Villejuif, France

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¹Epigenetics of Haematopoiesis Laboratory, Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom

²Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom

³Division of Hematology, National Taiwan University Hospital, Taipei, Taiwan

⁴Computational Biology Support Team, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom

⁵INSERM U1287, Gustave Roussy Cancer Center, Villejuif, France

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¹Epigenetics of Haematopoiesis Laboratory, Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom

²Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom

³Division of Hematology, National Taiwan University Hospital, Taipei, Taiwan

⁴Computational Biology Support Team, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom

⁵INSERM U1287, Gustave Roussy Cancer Center, Villejuif, France

Find articles by Lin, C. in: PubMed | Google Scholar

¹Epigenetics of Haematopoiesis Laboratory, Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom

²Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom

³Division of Hematology, National Taiwan University Hospital, Taipei, Taiwan

⁴Computational Biology Support Team, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom

⁵INSERM U1287, Gustave Roussy Cancer Center, Villejuif, France

Find articles by Tien, H. in: PubMed | Google Scholar

¹Epigenetics of Haematopoiesis Laboratory, Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom

²Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom

³Division of Hematology, National Taiwan University Hospital, Taipei, Taiwan

⁴Computational Biology Support Team, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom

⁵INSERM U1287, Gustave Roussy Cancer Center, Villejuif, France

Find articles by Sellers, R. in: PubMed | Google Scholar

¹Epigenetics of Haematopoiesis Laboratory, Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom

²Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom

³Division of Hematology, National Taiwan University Hospital, Taipei, Taiwan

⁴Computational Biology Support Team, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom

⁵INSERM U1287, Gustave Roussy Cancer Center, Villejuif, France

Find articles by Sahoo, S. in: PubMed | Google Scholar

¹Epigenetics of Haematopoiesis Laboratory, Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom

²Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom

³Division of Hematology, National Taiwan University Hospital, Taipei, Taiwan

⁴Computational Biology Support Team, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom

⁵INSERM U1287, Gustave Roussy Cancer Center, Villejuif, France

Find articles by Bonnet, D. in: PubMed | Google Scholar

¹Epigenetics of Haematopoiesis Laboratory, Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom

²Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom

³Division of Hematology, National Taiwan University Hospital, Taipei, Taiwan

⁴Computational Biology Support Team, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom

⁵INSERM U1287, Gustave Roussy Cancer Center, Villejuif, France

Find articles by Solary, E. in: PubMed | Google Scholar

¹Epigenetics of Haematopoiesis Laboratory, Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom

²Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom

³Division of Hematology, National Taiwan University Hospital, Taipei, Taiwan

⁴Computational Biology Support Team, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom

⁵INSERM U1287, Gustave Roussy Cancer Center, Villejuif, France

Find articles by Selimoglu-Buet, D. in: PubMed | Google Scholar

¹Epigenetics of Haematopoiesis Laboratory, Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom

²Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom

³Division of Hematology, National Taiwan University Hospital, Taipei, Taiwan

⁴Computational Biology Support Team, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom

⁵INSERM U1287, Gustave Roussy Cancer Center, Villejuif, France

Find articles by Wiseman, D. in: PubMed | Google Scholar

¹Epigenetics of Haematopoiesis Laboratory, Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom

²Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom

³Division of Hematology, National Taiwan University Hospital, Taipei, Taiwan

⁴Computational Biology Support Team, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom

⁵INSERM U1287, Gustave Roussy Cancer Center, Villejuif, France

Find articles by Batta, K. in: PubMed | Google Scholar

J Clin Invest. https://doi.org/10.1172/JCI201335.
Copyright © 2026, Hull et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published October 21, 2026 - Version history

Chronic myelomonocytic leukemia (CMML) is a hematological neoplasm characterized by expansion of malignant monocytes. However, as a stem cell neoplasm, the disease clone comprises most blood lineages, including granulocytes. To investigate their pathogenic contribution, we performed extensive phenotypic, transcriptomic and functional characterization of CMML granulocytes. These cells exhibited reduced granularity and impaired maturation, the latter of which is associated with poor prognosis. Functionally, CMML granulocytes displayed reduced phagocytic capacity and impaired NETosis, together with aberrant gene expression programs. Notably, RETN, encoding the chemokine resistin, was uniquely upregulated in CMML granulocytes. Accordingly, resistin levels were 10-fold higher in CMML plasma, correlating with inferior survival. Ex vivo exposure to resistin directly blocked monocyte maturation and macrophage differentiation, partly via TLR4 interaction, recapitulating the classical monocytosis repartitioning phenotype that characterizes CMML. Resistin-treated monocytes upregulated gene signatures related to immune suppression and myeloid-derived suppressor cell phenotype. Consistent with these findings, CMML patients displayed higher Treg proportions and Th2/Th1 ratios. Furthermore, we demonstrated that resistin directly skews the Th2/Th1 ratio via binding to monocytes. Thus, CMML granulocytes produce high levels of resistin, which contributes to defective monocyte maturation and induction of myeloid-derived suppressor cell features in monocytes, thereby fostering an immune-suppressive state in this disease.

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Granulocyte-derived Resistin Inhibits Monocyte Maturation and Promotes an Immunosuppressive Phenotype in Chronic Myelomonocytic Leukemia Monocytes

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Granulocyte-derived Resistin Inhibits Monocyte Maturation and Promotes an Immunosuppressive Phenotype in Chronic Myelomonocytic Leukemia Monocytes

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