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

Authors :
Ayala Tovy
Carina Rosas
Amos S. Gaikwad
Geraldo Medrano
Linda Zhang
Jaime M. Reyes
Yung-Hsin Huang
Tastuhiko Arakawa
Kristen Kurtz
Shannon E. Conneely
Anna G. Guzman
Rogelio Aguilar
Anne Gao
Chun-Wei Chen
Jean J. Kim
Melissa T. Carter
Amaia Lasa-Aranzasti
Irene Valenzuela
Lionel Van Maldergem
Lorenzo Brunetti
M. John Hicks
Andrea N. Marcogliese
Margaret A. Goodell
Rachel E. Rau
Source :
Haematologica, Vol 107, Iss 4 (2021)
Publication Year :
2021
Publisher :
Ferrata Storti Foundation, 2021.

Abstract

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.

Details

Language :
English
ISSN :
03906078 and 15928721
Volume :
107
Issue :
4
Database :
Directory of Open Access Journals
Journal :
Haematologica
Publication Type :
Academic Journal
Accession number :
edsdoj.6079e5ab657743e3ae91733b02a811e1
Document Type :
article
Full Text :
https://doi.org/10.3324/haematol.2021.278990