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Perturbed hematopoiesis in individuals with germline DNMT3A overgrowth Tatton-Brown-Rahman syndrome

Tatton-Brown-Rahman syndrome (TBRS) is an overgrowth disorder caused by germline heterozygous mutations in the DNA methyltransferase DNMT3A. DNMT3A is a critical regulator of hematopoietic stem cell (HSC) differentiation and somatic DNMT3A mutations are frequent in hematologic malignancies and clona...

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Autores principales: Tovy, Ayala, Rosas, Carina, Gaikwad, Amos S., Medrano, Geraldo, Zhang, Linda, Reyes, Jaime M., Huang, Yung-Hsin, Arakawa, Tatsuhiko, Kurtz, Kristen, Conneely, Shannon E., Guzman, Anna G., Aguilar, Rogelio, Gao, Anne, Chen, Chun-Wei, Kim, Jean J., Carter, Melissa T., Lasa-Aranzasti, Amaia, Valenzuela, Irene, Maldergem, Lionel Van, Brunetti, Lorenzo, Hicks, M. John, Marcogliese, Andrea N., Goodell, Margaret A., Rau, Rachel E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Fondazione Ferrata Storti 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8968878/
https://www.ncbi.nlm.nih.gov/pubmed/34092059
http://dx.doi.org/10.3324/haematol.2021.278990
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author Tovy, Ayala
Rosas, Carina
Gaikwad, Amos S.
Medrano, Geraldo
Zhang, Linda
Reyes, Jaime M.
Huang, Yung-Hsin
Arakawa, Tatsuhiko
Kurtz, Kristen
Conneely, Shannon E.
Guzman, Anna G.
Aguilar, Rogelio
Gao, Anne
Chen, Chun-Wei
Kim, Jean J.
Carter, Melissa T.
Lasa-Aranzasti, Amaia
Valenzuela, Irene
Maldergem, Lionel Van
Brunetti, Lorenzo
Hicks, M. John
Marcogliese, Andrea N.
Goodell, Margaret A.
Rau, Rachel E.
author_facet Tovy, Ayala
Rosas, Carina
Gaikwad, Amos S.
Medrano, Geraldo
Zhang, Linda
Reyes, Jaime M.
Huang, Yung-Hsin
Arakawa, Tatsuhiko
Kurtz, Kristen
Conneely, Shannon E.
Guzman, Anna G.
Aguilar, Rogelio
Gao, Anne
Chen, Chun-Wei
Kim, Jean J.
Carter, Melissa T.
Lasa-Aranzasti, Amaia
Valenzuela, Irene
Maldergem, Lionel Van
Brunetti, Lorenzo
Hicks, M. John
Marcogliese, Andrea N.
Goodell, Margaret A.
Rau, Rachel E.
author_sort Tovy, Ayala
collection PubMed
description Tatton-Brown-Rahman syndrome (TBRS) is an overgrowth disorder caused by germline heterozygous mutations in the DNA methyltransferase DNMT3A. DNMT3A is a critical regulator of hematopoietic stem cell (HSC) differentiation and somatic DNMT3A mutations are frequent in hematologic malignancies and clonal hematopoiesis. Yet, the impact of constitutive DNMT3A mutation on hematopoiesis in TBRS is undefined. In order to establish how constitutive mutation of DNMT3A impacts blood development in TBRS we gathered clinical data and analyzed blood parameters in 18 individuals with TBRS. We also determined the distribution of major peripheral blood cell lineages by flow cytometric analyses. Our analyses revealed non-anemic macrocytosis, a relative decrease in lymphocytes and increase in neutrophils in TBRS individuals compared to unaffected controls. We were able to recapitulate these hematologic phenotypes in multiple murine models of TBRS and identified rare hematological and non-hematological malignancies associated with constitutive Dnmt3a mutation. We further show that loss of DNMT3A in TBRS is associated with an altered DNA methylation landscape in hematopoietic cells affecting regions critical to stem cell function and tumorigenesis. Overall, our data identify key hematopoietic effects driven by DNMT3A mutation with clinical implications for individuals with TBRS and DNMT3A-associated clonal hematopoiesis or malignancies.
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spelling pubmed-89688782022-04-11 Perturbed hematopoiesis in individuals with germline DNMT3A overgrowth Tatton-Brown-Rahman syndrome Tovy, Ayala Rosas, Carina Gaikwad, Amos S. Medrano, Geraldo Zhang, Linda Reyes, Jaime M. Huang, Yung-Hsin Arakawa, Tatsuhiko Kurtz, Kristen Conneely, Shannon E. Guzman, Anna G. Aguilar, Rogelio Gao, Anne Chen, Chun-Wei Kim, Jean J. Carter, Melissa T. Lasa-Aranzasti, Amaia Valenzuela, Irene Maldergem, Lionel Van Brunetti, Lorenzo Hicks, M. John Marcogliese, Andrea N. Goodell, Margaret A. Rau, Rachel E. Haematologica Article Tatton-Brown-Rahman syndrome (TBRS) is an overgrowth disorder caused by germline heterozygous mutations in the DNA methyltransferase DNMT3A. DNMT3A is a critical regulator of hematopoietic stem cell (HSC) differentiation and somatic DNMT3A mutations are frequent in hematologic malignancies and clonal hematopoiesis. Yet, the impact of constitutive DNMT3A mutation on hematopoiesis in TBRS is undefined. In order to establish how constitutive mutation of DNMT3A impacts blood development in TBRS we gathered clinical data and analyzed blood parameters in 18 individuals with TBRS. We also determined the distribution of major peripheral blood cell lineages by flow cytometric analyses. Our analyses revealed non-anemic macrocytosis, a relative decrease in lymphocytes and increase in neutrophils in TBRS individuals compared to unaffected controls. We were able to recapitulate these hematologic phenotypes in multiple murine models of TBRS and identified rare hematological and non-hematological malignancies associated with constitutive Dnmt3a mutation. We further show that loss of DNMT3A in TBRS is associated with an altered DNA methylation landscape in hematopoietic cells affecting regions critical to stem cell function and tumorigenesis. Overall, our data identify key hematopoietic effects driven by DNMT3A mutation with clinical implications for individuals with TBRS and DNMT3A-associated clonal hematopoiesis or malignancies. Fondazione Ferrata Storti 2021-06-03 /pmc/articles/PMC8968878/ /pubmed/34092059 http://dx.doi.org/10.3324/haematol.2021.278990 Text en Copyright© 2022 Ferrata Storti Foundation https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
spellingShingle Article
Tovy, Ayala
Rosas, Carina
Gaikwad, Amos S.
Medrano, Geraldo
Zhang, Linda
Reyes, Jaime M.
Huang, Yung-Hsin
Arakawa, Tatsuhiko
Kurtz, Kristen
Conneely, Shannon E.
Guzman, Anna G.
Aguilar, Rogelio
Gao, Anne
Chen, Chun-Wei
Kim, Jean J.
Carter, Melissa T.
Lasa-Aranzasti, Amaia
Valenzuela, Irene
Maldergem, Lionel Van
Brunetti, Lorenzo
Hicks, M. John
Marcogliese, Andrea N.
Goodell, Margaret A.
Rau, Rachel E.
Perturbed hematopoiesis in individuals with germline DNMT3A overgrowth Tatton-Brown-Rahman syndrome
title Perturbed hematopoiesis in individuals with germline DNMT3A overgrowth Tatton-Brown-Rahman syndrome
title_full Perturbed hematopoiesis in individuals with germline DNMT3A overgrowth Tatton-Brown-Rahman syndrome
title_fullStr Perturbed hematopoiesis in individuals with germline DNMT3A overgrowth Tatton-Brown-Rahman syndrome
title_full_unstemmed Perturbed hematopoiesis in individuals with germline DNMT3A overgrowth Tatton-Brown-Rahman syndrome
title_short Perturbed hematopoiesis in individuals with germline DNMT3A overgrowth Tatton-Brown-Rahman syndrome
title_sort perturbed hematopoiesis in individuals with germline dnmt3a overgrowth tatton-brown-rahman syndrome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8968878/
https://www.ncbi.nlm.nih.gov/pubmed/34092059
http://dx.doi.org/10.3324/haematol.2021.278990
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