DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions

Abstract

Age-associated clonal hematopoiesis caused by acquired mutations in myeloid cancer-associated genes is highly prevalent in the normal population. Its etiology, biological impact on hematopoiesis, and oncogenic risk is poorly defined at this time. To gain insight into this phenomenon, we analyzed a cohort of 2530 related and unrelated hematologically normal individuals (ages 55 to 101 years). We used a sensitive gene-targeted deep sequencing approach to gain precision on the exact prevalence of driver mutations and the proportions of affected genes. Mutational status was correlated with biological parameters. We report a higher overall prevalence of driver mutations (13.7%), which occurred mostly (93%) in or and were highly age-correlated. Mutation in these 2 genes had some distinctive effects on end points. mutations were more age-dependent, associated with a modest neutropenic effect (9%, = .012), demonstrated familial aggregation, and associated with chronic obstructive pulmonary disease. Mutations in had no impact on blood counts or indices. Mutational burden of both genes correlated with X-inactivation skewing but no significant association with age-adjusted telomere length reduction was documented. The discordance between the high prevalence of mutations in these 2 genes and their limited biological impact raise the question of the potential role of dysregulated epigenetic modifiers in normal aging hematopoiesis, which may include support to failing hematopoiesis.

TET enzymes control antibody production and shape the mutational landscape in germinal centre B cells

“…This is consistent with a comparable fraction of apoptotic cells (Fig. This is in line with Dominguez et al [46] who propose that low TET2 levels, such as in patients with clonal hematopoiesis of indeterminate potential that present with TET2 loss-of-function mutations [47], prevent terminal differentiation hence facilitating B lymphomagenesis. To confirm in an independent culture system that TET-deficiency does not impact the proliferation of activated B cells, na€ ıve B cells were labelled with a proliferation-tracking dye and stimulated with aCD40/IL-4/IL-21 or LPS/IL-4/IL-5.…”

Clonal hematopoiesis and preleukemia—Genetics, biology, and clinical implications

“…The frequency of CH was age‐dependent: Somatic gene mutations were rarely identified in persons younger than 50 years, while CH was identified in about 10% of persons aged >65 years and in as many as 18% of those over the age of 90 years. The frequency of CH is even considerably higher when more sensitive methods are used to reveal gene mutations at very low variant allele frequencies (VAFs), allowing the detection of small clones of blood cells . For instance, Young et al detected CH in 19/20 individuals aged between 50 and 60 years using an error‐corrected sequencing approach that allowed detection of mutations with VAFs as low as 0.03% .…”

Clonal hematopoiesis of indeterminate potential–associated mutations and risk of comorbidities in patients with myelodysplastic syndrome

“…As in MDS, CHIP is more frequent with advancing age. The most commonly mutated genes associated with CHIP are DNA methyltransferase 3α (DNMT3A ), ASXL transcriptional regulator 1 ( ASXL1 ), tet methylcytosine dioxygenase 2 ( TET2 ), tumor protein 53 ( TP53 ), Janus kinase 1 ( JAK2 ), and splicing factor 3b subunit 1 ( SF3B1 ) . In MDS, mutations in TET2 , ASXL1 , and DNMT3A have been noted in >10% of cases …”