Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis

Busque, Lambert; Patel, Jay P.; Figueroa, María E.; Vasanthakumar, Aparna; Provost, Sylvie; Hamilou, Zineb; Mollica, Luigina; Li, Juan; Viale, Agnès; Heguy, Adriana; Hassimi, Maryam; Socci, Nicholas D.; Bhatt, Parva; Gönen, Mithat; Mason, Christopher E.; Melnick, Ari; Godley, Lucy A.; Brennan, Cameron; Abdel-Wahab, Omar; Levine, Ross L.

doi:10.1038/ng.2413

Cited by 712 publications

(601 citation statements)

References 13 publications

Supporting

Mentioning

558

Contrasting

Unclassified

Order By: Relevance

“…Such variants are typically present in a proportion of peripheral blood cells at a specific time-point but their frequency can increase or decrease over time and even disappear, suggesting a dynamic pattern of clonal change 1 . Consistent with this data, mutations in genes that are often mutated in myeloid malignancy such as TET2, DNMT3A, ASXL1 and JAK2 have also been described in elderly individuals with no evidence of hematological malignancy [5][6][7][8] . Increasing age is accompanied by changes to the hematopoietic stem cell (HSC) compartment, a process known as myeloid shift, with a bias towards the myeloid lineage at the expense of the lymphoid lineage 9 .…”

Section: Detection Of Leukemia-associated Mutations In Peripheral Blosupporting

confidence: 75%

Detection of leukemia-associated mutations in peripheral blood DNA of hematologically normal elderly individuals

et al. 2015

View full text Add to dashboard Cite

Section: Detection Of Leukemia-associated Mutations In Peripheral Blosupporting

confidence: 75%

Detection of leukemia-associated mutations in peripheral blood DNA of hematologically normal elderly individuals

et al. 2015

View full text Add to dashboard Cite

“…Both muta tions and deletions of the TET2 gene have been frequently observed in patients, with mutations occurring in 13% and deletions in approximately 3% [27,44,45]. A recent finding has shed more light on the function of TET2, where somatic mutations were found in normal elderly individuals pre senting with clonal hematopoiesis [50]. This discovery, alongside the mouse studies, supports the notion that TET2 enhances self renewal and clonal expansion in stem cells.…”

Section: Epigenetic Factor Mutationssupporting

confidence: 62%

Molecular basis and clonal evolution of myeloproliferative neoplasms

Cleary

Královics

2013

Clinical Chemistry and Laboratory Medicine (CCLM)

View full text Add to dashboard Cite

Myeloproliferative neoplasms (MPNs) repre sent a group of diseases that affect the myeloid lineage, characterized by the presence of an excess of terminally differentiated myeloid cells. Defects causing clonal hematopoiesis are a key factor in the emergence of these diseases. Throughout the years, a number of causative defects have been identified, predominantly affecting cytokine signaling and gene expression regulation. This review aims to provide an update on the current status of the MPN field in relation to identification of molecular defects involved in the disease and its clonal evolution.

show abstract

“…19,20,43,44 Busque et al reported TET2 mutations in PNMs (not in lymphoid cells) from 10 of 182 (5.6%) elderly women (.65 years old) with NRXI, but not in 95 younger women (,60 years old) or 105 elderly women without NRXI. 71 More comprehensive surveys of leukemia/ MDS-associated mutations in the general population were conducted by repurposing WES data of peripheral blood DNA from large population-based studies. Jaiswal et al focused on 160 candidate mutational targets reported in hematologic cancers and found mutations in 73 genes in 746 of 17 182 participants.…”

Section: Age-related Ch In the General Populationmentioning

confidence: 99%

Clonal hematopoiesis in acquired aplastic anemia

Ogawa

2016

Blood

156

130

View full text Add to dashboard Cite

Clonal hematopoiesis (CH) in aplastic anemia (AA) has been closely linked to the evolution of late clonal disorders, including paroxysmal nocturnal hemoglobinuria and myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML), which are common complications after successful immunosuppressive therapy (IST). With the advent of high-throughput sequencing of recent years, the molecular aspect of CH in AA has been clarified by comprehensive detection of somatic mutations that drive clonal evolution. Genetic abnormalities are found in ∼50% of patients with AA and, except for PIGA mutations and copy-neutral loss-of-heterozygosity, or uniparental disomy (UPD) in 6p (6pUPD), are most frequently represented by mutations involving genes commonly mutated in myeloid malignancies, including DNMT3A, ASXL1, and BCOR/BCORL1. Mutations exhibit distinct chronological profiles and clinical impacts. BCOR/BCORL1 and PIGA mutations tend to disappear or show stable clone size and predict a better response to IST and a significantly better clinical outcome compared with mutations in DNMT3A, ASXL1, and other genes, which are likely to increase their clone size, are associated with a faster progression to MDS/AML, and predict an unfavorable survival. High frequency of 6pUPD and overrepresentation of PIGA and BCOR/BCORL1 mutations are unique to AA, suggesting the role of autoimmunity in clonal selection. By contrast, DNMT3A and ASXL1 mutations, also commonly seen in CH in the general population, indicate a close link to CH in the aged bone marrow, in terms of the mechanism for selection. Detection and close monitoring of somatic mutations/evolution may help with prediction and diagnosis of clonal evolution of MDS/AML and better management of patients with AA.

show abstract

Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis

Cited by 712 publications

References 13 publications

Detection of leukemia-associated mutations in peripheral blood DNA of hematologically normal elderly individuals

Detection of leukemia-associated mutations in peripheral blood DNA of hematologically normal elderly individuals

Molecular basis and clonal evolution of myeloproliferative neoplasms

Clonal hematopoiesis in acquired aplastic anemia

Contact Info

Product

Resources

About