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DOI: 10.1055/s-0042-1748686
A meningeal preleukemic niche promotes the homing of B-cell Precursor Acute Lymphoblastic Leukaemia cells to the CNS
Aim To understand early events promoting the engraftment and homing of BCP-ALL cells to the CNS in order to identify potential therapeutic interventions.
Methods We determined in vivo engraftment kinetics of luciferase+ BCP-ALL patient derived xenograft (PDX) cells in NSG-mice and subjected healthy vs pre-leukemic meninges to RNA-sequencing. Potential preleukemic niche (PLN) associated factors were validated in vitro using CRISPR-CAS9 editing of CNS “stroma” cell lines in CNS/ALL-cocultures.
Results Comparative RNA-sequencing showed an upregulation of inflammation and adhesion pathways and molecules previously shown to be associated with CNS-leukemia (e.g. IL7, CXCL12) in preleukemic meninges. In vitro coculture of the CNS-tropic cell lines REH and NALM6 with BEND3, BMEC cells and primary murine meningeal fibroblasts resulted in a significant upregulation of VCAM1 in the CNS stroma. Knockdown of VCAM1 in CNS cells resulted in a reduced release of proinflammatory chemokines in cocultures.
Conclusion BCP-ALL cells may induce alterations in murine meninges promoting a PLN in the CNS. This may open the window for novel targeted interventions and early diagnosis in CNS-leukemia.
Publication History
Article published online:
17 May 2022
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