Myeloproliferative neoplasms (MPNs) arise from a single hematopoietic stem cell (HSC) that acquires a driver mutation, often decades prior to clinical manifestations [1]. The most common driver mutation, JAK2^V617F, activates aberrant JAK/STAT signaling via receptors critical for myelopoiesis [2]. Over time, this MPN HSC clone outcompetes its normal counterparts, leading to excessive myeloid cell production. However, lymphopenia is also seen in patients with MPNs [3, 4] and contributes to elevated neutrophil-to-lymphocyte ratio (NLR), which predicts disease-related complications including thrombosis and mortality [5, 6]. We conducted this study to learn how JAK2^V617F hematopoiesis affects lymphoid differentiation in MPNs.

To assess the effect of JAK2^V617F on hematopoiesis in our MPN cohort, we measured JAK2^V617F mutation allele frequency (MAF) by droplet digital PCR in hematopoietic subsets fractionated from peripheral blood (PB) by fluorescence activated cell sorting (FACS). MAF increased in HSCs and multipotent progenitors (HSC/MPPs, CD45^dimCD34⁺CD38^-CD45RA^-) by 1.6% (±0.5%) per year of MPN duration (Fig. 1B). Despite this progressive dominance of JAK2^V617F hematopoiesis, JAK2^V617F was largely absent from lymphocytes (Fig. 1C and Supplementary Fig. 1) as previously reported [9]. Thus, inadequate lymphopoiesis may drive lymphopenia in JAK2^V617F MPNs.

骨髓增生性肿瘤（myeloproliferative neoplasm， MPN）起源于单个造血干细胞（hematopoietic stem cell， HSC），该干细胞通常比临床表现早几十年发生驱动突变[1]。最常见的驱动突变 JAK2^V617F 通过对骨髓生成至关重要的受体激活异常的 JAK/STAT 信号传导 [2]。随着时间的推移，这种 MPN HSC 克隆优于其正常克隆，导致髓系细胞产生过多。然而，淋巴细胞减少也见于 MPN 患者 [3， 4]，并导致中性粒细胞与淋巴细胞比值 （NLR） 升高，从而预测疾病相关并发症，包括血栓形成和死亡率 [5， 6]。我们进行了这项研究，以了解 JAK2^V617F 造血如何影响 MPN 中的淋巴分化。

为了评估 JAK2^V617F 对 MPN 队列造血的影响，我们通过液滴数字 PCR 测量了 JAK2^V617F 突变等位基因频率 （MAF），通过荧光激活细胞分选 （FACS） 从外周血 （PB） 中分离出来的造血亚群。HSC 和多能祖细胞 （HSC/MPPs、CD45^dimCD34⁺CD38-CD45RA^-） 的 MAF 在 MPN 持续时间内每年增加 1.6% （±0.5%） （图 1B）。尽管 JAK2^V617F 造血具有这种进行性优势，但正如先前报道的那样，JAK2^V617F 在淋巴细胞中基本不存在 （图 1C 和补充图 1） [9]。因此，淋巴细胞生成不足可能导致 JAK2^V617F MPN 中出现淋巴细胞减少。