Niche Heterogeneity Impacts Evolution of Myeloproliferative Neoplasms Driven By the Same Oncogenic Pathway

Different MPNs have distinct rates of malignant transformation (PMF>PV>ET). Although PV and ET can arise from hematopoietic stem/progenitor cells (HSPCs) with similarly activated JAK-STAT oncogenic pathway, the transformation rate into secondary myelofibrosis and leukemia is higher for PV than for ET. However, the underlying reasons are not fully clear. Whereas in some cases secondary mutations might cause transformation, it remains unclear whether distinct bone marrow (BM) microenvironments can influence the progression of MPNs or any preleukemic disorder. Previous studies have suggested that normal BM niches close to bone (endosteal) promote HSPC quiescence, whereas non-endosteal vessels permit transmigration of activated HSPCs. We hypothesized that PV and ET HSPCs might expand in different BM niches, which could thereby influence disease progression.To address this question, we performed combined two-photon and confocal real-time intravital microscopy in the skull BM of WT mice transplanted with HSPCs from WT mice or MPN mice carrying the same driver mutation (JAK2V617F) but showing phenotypically distinct diseases (ET or PV). ET HSPCs resembled WT HSPCs in their homing and engraftment near bone (22±15 and 26±13 μm, respectively) 3 days after i.v. injection into lethally-irradiated WT mice. In contrast, PV HSPCs located significantly further (31±21 μm) from bone, which was independently confirmed in a distinct PV model. The different homing...

Source: Blood - November 21, 2018 Category: Hematology Authors: Korn, C., Rak, J., Garcia-Garcia, A., Fielding, C., Khorshed, R., Gonzalez-Anton, S., Li, J., Norfo, R., Baxter, E. J., McKerrell, T., Roberts, T., Eldaly, H., Godfrey, A. L., Castillo-Venzor, A., Kusumbe, A., Mead, A. J., Green, A. R., Kent, D., Lo Celso Tags: 635. Myeloproliferative Syndromes: Basic Science: Mechanisms of Development and Progression Source Type: research