Lineage restriction analyses in CHIP indicate myeloid bias for TET2 and multipotent stem cell origin for DNMT3A
Lineage restriction analyses in CHIP indicate myeloid bias for TET2 and multipotent stem cell origin for DNMT3A
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DOI：
10.1182/blood-2018-01-829937
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发表时间：
2018-07-19
期刊：
影响因子：
20.3
通讯作者：
Busque, Lambert
中科院分区：
文献类型：
--
作者：
Buscarlet, Manuel;Provost, Sylvie;Busque, Lambert
我们分析了107例克隆性造血潜能不确定（CHIP）患者的多形核细胞（PMN）、单核细胞、B细胞和T细胞的DNA，以进行不同基因突变的谱系限制性分析。定义了三种谱系类别：髓样（含或不含单核细胞的PMN）、髓淋巴-B（髓样和B细胞）和多能（髓样、B和T细胞）。6个具有异常模式的个体被排除在分析之外。其中94例有单一突变（DNMT 3A 56例，TET 2 24例，其他基因7例[JAK 2，ASXL 1，CBL或TP 53]）。14个有多重突变。单个DNMT 3A或TET 2突变个体的谱系限制模式是不同的。TET 2的髓系限制性突变比例（54.2%，13/24）高于DNMT 3A（23.2%，13/56）（P <0.05）。这与髓淋巴细胞B类相似，但TET 2个体的髓样细胞比例高1.5倍（P <0.05）。重要的是，0%（0/24）的TET 2突变个体在多能类别中，而DNMT 3A突变个体为35.7%（20/56）（P < .01）。克隆大小预测DNMT 3A的多能模式，表明广泛谱系克隆优势的时间延迟。这些独特的特征可能是重要的，在破译这些频繁的突变的转化机制。
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 DNMT3A, 24 in TET2, 7 in other genes [JAK2, ASXL1, CBL or TP53]). Fourteen 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 of 24) than for DNMT3A (23.2%, 13 of 56) (P < .05). It was similar for myelolympho-B category but with a 1.5 fold greater proportion of myeloid cells for TET2 individuals (P < .05). Importantly, 0% (0 of 24) of the individuals with TET2 mutation in the multipotent category in contrast to 35.7% (20 of 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.