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Lineage restriction analyses in CHIP indicate myeloid bias for TET2 and multipotent stem cell origin for DNMT3A

Manuel Buscarlet, Sylvie Provost, Yassamin Feroz Zada, Vincent Bourgoin, Luigina Mollica, Marie-Pierre Dubé and Lambert Busque

Key points

  • TET2 mutations confer a myeloid proliferation bias

  • DNMT3A mutations occur in a multipotent stem cell

Abstract

We analyzed DNA from PMN (granulocytes), CD14+ (monocytes), CD19+ (B-cells) and CD3+ (T-cells) of 107 individuals with clonal hematopoiesis of indeterminate potential (CHIP) to perform lineage restriction analysis of different gene mutations. Individuals were aged 55 to 96 (mean age: 70.0). Three lineage categories were defined: myeloid (PMN±monocytes), myelolympho-B (myeloid and B-cells), multipotent (myeloid, B and T-cells). Six individuals with aberrant patterns were excluded from analysis. Fifty-six had a single DNMT3A mutation, 24 had a single TET2 mutation, 7 had a single mutation in other genes (JAK2, ASXL1, CBL or TP53), and 14 had multiple mutations. The lineage restriction patterns of single DNMT3A or TET2 mutated individuals were different. The proportion of myeloid restricted mutations was higher for TET2 (54.2%, 13/24) than for DNMT3A (23.2%, 13/56) (P<.05). It was similar for myelolympho-B but with a 1.5 fold greater proportion of myeloid cells for TET2 individuals (P<.05). Importantly, there was 0% (0/24) individuals with TET2 mutation in the multipotent category in contrast to 35.7% (20/56) for DNMT3A (P<.01). The clone size predicted multipotent pattern for DNMT3A suggesting a time delay for extensive lineage clonal dominance. These distinctive features may be important in deciphering the transformation mechanisms of these frequent mutations.

  • Submitted January 29, 2018.
  • Accepted May 9, 2018.