Mesenchymal stromal cells (MSC) from JAK2+ myeloproliferative neoplasms differ from normal MSC and contribute to the maintenance of neoplastic hematopoiesis

There is evidence of continuous bidirectional cross-talk between malignant cells and bone marrow-derived mesenchymal stromal cells (BM-MSC), which favors the emergence and progression of myeloproliferative neoplastic (MPN) diseases. In the current work we have compared the function and gene expression profile of BM-MSC from healthy donors (HD-MSC) and patients with MPN (JAK2V617F), showing no differences in the morphology, proliferation and differentiation capacity between both groups. However, BM-MSC from MPN expressed higher mean fluorescence intensity (MIF) of CD73, CD44 and CD90, whereas CD105 was lower when compared to controls. Gene expression profile of BM-MSC showed a total of 169 genes that were differentially expressed in BM-MSC from MPN patients compared to HD-MSC. In addition, we studied the ability of BM-MSC to support the growth and survival of hematopoietic stem/progenitor cells (HSPC), showing a significant increase in the number of CFU-GM colonies when MPN-HSPC were co-cultured with MPN-MSC. Furthermore, MPN-MSC showed alteration in the expression of genes associated to the maintenance of hematopoiesis, with an overexpression of SPP1 and NF-kB, and a downregulation of ANGPT1 and THPO. Our results suggest that BM-MSC from JAK2+ patients differ from their normal counterparts and favor the maintenance of malignant clonal hematopoietic cells.已有研究证实，恶性细胞与骨髓来源间充质基质细胞（BM-MSC）之间存在持续的双向交叉对话，该过程可促进骨髓增殖性肿瘤（MPN）的发生与进展。本研究对比了健康供者来源BM-MSC（HD-MSC）与携带JAK2V617F突变的MPN患者来源BM-MSC的功能与基因表达谱，结果显示两组细胞在形态学、增殖能力及分化潜能上均无显著差异。然而，与健康对照组相比，MPN患者来源BM-MSC的CD73、CD44及CD90的平均荧光强度（MIF）更高，而CD105的平均荧光强度则更低。BM-MSC的基因表达谱分析显示，与健康供者来源BM-MSC相比，MPN患者来源BM-MSC中共有169个差异表达基因。此外，本研究还探讨了BM-MSC支持造血干/祖细胞（HSPC）生长与存活的能力，结果发现当MPN来源HSPC与MPN来源BM-MSC共培养时，CFU-GM集落的数量显著增加。进一步研究显示，MPN来源BM-MSC的造血维持相关基因表达存在异常：SPP1与NF-κB呈过表达，而ANGPT1与THPO则呈现下调。本研究结果表明，携带JAK2突变的MPN患者来源BM-MSC与健康供者来源BM-MSC存在显著差异，且可促进恶性克隆性造血细胞的存活与维持。