JAK2V617F impairs lymphoid differentiation in myeloproliferative neoplasms

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.