TMPRSS6 as a Therapeutic Target for Disorders of Erythropoiesis and Iron Homeostasis

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Abstract

TMPRSS6 is a serine protease highly expressed in the liver. Its role in iron regulation was first reported in 2008 when mutations in TMPRSS6 were shown to be the cause of iron-refractory iron deficiency anemia (IRIDA) in humans and in mouse models. TMPRSS6 functions as a negative regulator of the expression of the systemic iron-regulatory hormone hepcidin. Over the last decade and a half, growing understanding of TMPRSS6 biology and mechanism of action has enabled development of new therapeutic approaches for patients with diseases of erythropoiesis and iron homeostasis.

ClinicalTrials.gov identifier NCT03165864.

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The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.

Daniel Arber, Attilio Orazi, Robert P. Hasserjian … (2016)

The World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues was last updated in 2008. Since then, there have been numerous advances in the identification of unique biomarkers associated with some myeloid neoplasms and acute leukemias, largely derived from gene expression analysis and next-generation sequencing that can significantly improve the diagnostic criteria as well as the prognostic relevance of entities currently included in the WHO classification and that also suggest new entities that should be added. Therefore, there is a clear need for a revision to the current classification. The revisions to the categories of myeloid neoplasms and acute leukemia will be published in a monograph in 2016 and reflect a consensus of opinion of hematopathologists, hematologists, oncologists, and geneticists. The 2016 edition represents a revision of the prior classification rather than an entirely new classification and attempts to incorporate new clinical, prognostic, morphologic, immunophenotypic, and genetic data that have emerged since the last edition. The major changes in the classification and their rationale are presented here.

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IDENTIFICATION OF ERYTHROFERRONE AS AN ERYTHROID REGULATOR OF IRON METABOLISM

Léon Kautz, Grace Jung, Erika V. Valore … (2014)

Recovery from blood loss requires a greatly enhanced supply of iron to support expanded erythropoiesis. After hemorrhage, suppression of the iron-regulatory hormone hepcidin allows increased iron absorption and mobilization from stores. We identified a new hormone, erythroferrone (ERFE), which mediates hepcidin suppression during stress erythropoiesis. ERFE is produced by erythroblasts in response to erythropoietin. ERFE-deficient mice fail to suppress hepcidin rapidly after hemorrhage and exhibit a delay in recovery from blood loss. ERFE expression is greatly increased in murine HbbTh3/+ thalassemia intermedia where it contributes to the suppression of hepcidin and systemic iron overload characteristic of this disease.

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Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA).

John Strouse, Matthew M Heeney, Dean R Campagna … (2008)

Iron deficiency is usually attributed to chronic blood loss or inadequate dietary intake. Here, we show that iron deficiency anemia refractory to oral iron therapy can be caused by germline mutations in TMPRSS6, which encodes a type II transmembrane serine protease produced by the liver that regulates the expression of the systemic iron regulatory hormone hepcidin. These findings demonstrate that TMPRSS6 is essential for normal systemic iron homeostasis in humans.

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Author and article information

Contributors

Tomas Ganz:

ORCID: http://orcid.org/0000-0002-2830-5469

Tganz@mednet.ucla.edu

Terrance D. Barrett: TBarrett@ionisph.com

Journal

Journal ID (nlm-ta): Adv Ther

Journal ID (iso-abbrev): Adv Ther

Title: Advances in Therapy

Publisher: Springer Healthcare (Cheshire )

ISSN (Print): 0741-238X

ISSN (Electronic): 1865-8652

Publication date (Electronic): 23 January 2023

Publication date PMC-release: 23 January 2023

Publication date (Print): 2023

Volume: 40

Issue: 4

Pages: 1317-1333

Affiliations

[1 ]GRID grid.19006.3e, ISNI 0000 0000 9632 6718, Department of Medicine and Pathology, David Geffen School of Medicine, , University of California, ; Los Angeles, CA 90095 USA

[2 ]GRID grid.19006.3e, ISNI 0000 0000 9632 6718, Department of Medicine, , University of California, ; Los Angeles, CA 90095 USA

[3 ]GRID grid.239552.a, ISNI 0000 0001 0680 8770, Department of Pediatrics, Division of Hematology, , Children’s Hospital of Philadelphia (CHOP), ; 3401 Civic Center Boulevard, Philadelphia, PA 19104 USA

[4 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Cell and Molecular Biology Graduate Group (CAMB), , University of Pennsylvania, Abramson Research Center, ; 3615 Civic Center Boulevard, Room 316B, Philadelphia, PA 19104 USA

[5 ]Prilenia Therapeutics, Herzliya, Israel

[6 ]GRID grid.282569.2, ISNI 0000 0004 5879 2987, Ionis Pharmaceuticals, Inc., ; Carlsbad, CA USA

Author information

Tomas Ganz http://orcid.org/0000-0002-2830-5469

Article

Publisher ID: 2421

DOI: 10.1007/s12325-022-02421-w

PMC ID: 10070284

PubMed ID: 36690839

SO-VID: b6e26f67-207b-42c0-9270-bae57a86f003

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Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

History

Date received : 5 November 2022

Date accepted : 23 December 2022

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Keywords: iron restriction,iron overload,hemochromatosis,ineffective erythropoiesis,thalassemia

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Keywords: iron restriction, iron overload, hemochromatosis, ineffective erythropoiesis, thalassemia

TMPRSS6 as a Therapeutic Target for Disorders of Erythropoiesis and Iron Homeostasis

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cGMP: Generators, Effectors and Therapeutic Implications Conference

Most cited references 74

The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.

IDENTIFICATION OF ERYTHROFERRONE AS AN ERYTHROID REGULATOR OF IRON METABOLISM

Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA).

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