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

Abstract

We analyzed DNA from polymorphonuclear (PMN) cells, monocytes, B cells, and T cells of 107 individuals with clonal hematopoiesis of indeterminate potential (CHIP) to perform lineage restriction analysis of different gene mutations. Three lineage categories were defined: myeloid (PMN with or without monocytes), myelolympho-B (myeloid and B cells), and multipotent (myeloid, B and T cells). Six individuals with aberrant patterns were excluded from analysis. Ninety-four had a single mutation (56 in <i>DNMT3A</i>, 24 in <i>TET2</i>, 7 in other genes [<i>JAK2</i>, <i>ASXL1</i>, <i>CBL</i> or <i>TP53</i>]). Fourteen had multiple mutations. The lineage restriction patterns of single <i>DNMT3A</i>- or <i>TET2</i>-mutated individuals were different. The proportion of myeloid restricted mutations was higher for <i>TET2</i> (54.2%, 13 of 24) than for <i>DNMT3A</i> (23.2%, 13 of 56) (<i>P</i> < .05). It was similar for myelolympho-B category but with a 1.5 fold greater proportion of myeloid cells for <i>TET2</i> individuals (<i>P</i> < .05). Importantly, 0% (0 of 24) of the individuals with <i>TET2</i> mutation in the multipotent category in contrast to 35.7% (20 of 56) for <i>DNMT3A</i> (<i>P</i> < .01). The clone size predicted multipotent pattern for <i>DNMT3A</i> suggesting a time delay for extensive lineage clonal dominance. These distinctive features may be important in deciphering the transformation mechanisms of these frequent mutations.