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Abstract
Bone marrow (BM) fibrosis in myeloproliferative neoplasms (MPNs) is associated with a poor prognosis. The development of myelofibrosis and differentiation of mesenchymal stromal cells to profibrotic myofibroblasts depends on macrophages. Here, we compared macrophage frequencies in BM biopsies of MPN patients and controls (patients with non-neoplastic processes), including primary myelofibrosis (PMF, n = 18), essential thrombocythemia (ET, n = 14), polycythemia vera (PV, n = 12), and Philadelphia chromosome–positive chronic myeloid leukemia (CML, n = 9). In PMF, CD68-positive macrophages were greatly increased compared to CML (p = 0.017) and control BM (p < 0.001). Similar findings were observed by CD163 staining (PMF vs. CML: p = 0.017; PMF vs. control: p < 0.001). Moreover, CD68-positive macrophages were increased in PV compared with ET (p = 0.009) and reactive cases (p < 0.001). PMF had higher frequencies of macrophages than PV (CD68: p < 0.001; CD163: p < 0.001) and ET (CD68: p < 0.001; CD163: p < 0.001). CD163 and CD68 were often co-expressed in macrophages with stellate morphology in Philadelphia chromosome–negative MPN, resulting in a sponge-like reticular network that may be a key regulator of unbalanced hematopoiesis in the BM space and may explain differences in cellularity and clinical course.
Highlights
Classical myeloproliferative neoplasms (MPNs) are a heterogenous group of diseases arising from the bone marrow (BM), comprising Philadelphia chromosome (Ph)–positive chronic myeloid leukemia (CML) and the three Ph-negative (Ph−) MPN polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF)
PMF and CML (p = 0.017, false discovery rate (FDR) = 0.025), PMF and ET (p < 0.001, FDR = 0.005), PMF and PV (p < 0.001, FDR = 0.013), and PMF compared with reactive BM (p < 0.001, FDR = 0.010) (Fig. 2b)
The above results underline the importance of macrophages in MPN-associated alterations of the immune tumor microenvironment (TME) and regulation of cell lineage turn over
Summary
Classical myeloproliferative neoplasms (MPNs) are a heterogenous group of diseases arising from the bone marrow (BM), comprising Philadelphia chromosome (Ph)–positive chronic myeloid leukemia (CML) and the three Ph-negative (Ph−) MPN polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). While the Philadelphia-chromosomal BCR-ABL1 translocation is driving predominantly myeloid hyperplasia in CML, Ph− MPNs are driven by JAK-STAT signaling which is upregulated by different mutations (JAK2V617F, CALR, or MPLW515) and is a key event in the disease course [1, 2]. Enhanced JAK-STAT signaling leads to the release of proinflammatory and profibrotic cytokines [3] and chronic inflammation is considered as a major promoter of Ph− MPNs [4, 5]. The most important producers of profibrotic cytokines are megakaryocytes and macrophages [7]
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