1045 - LYN kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-JUN and THBS1

Non-hematopoietic stromal cells of the tumor microenvironment (TME) are increasingly recognized for facilitating disease progression and resistance to therapy in various lymphomas. In CLL, these stromal cells have an activated phenotype allowing for the diverse support of leukemic cells, e.g. via cytokines and direct cell contact. Here we demonstrate that an increased expression of LYN kinase in stromal cells of the CLL-TME stimulates their leukemia-promoting polarization and thus supports leukemic progression:

We previously discovered that LYN kinase promotes the formation of a supportive leukemic niche.
ImagingMassCytomety analysis of primary CLL lymph node samples revealed a significantly increased expression of LYN kinase especially within fibroblasts in the leukemic microenvironment. The absence of LYN in non-hematopoietic stromal cells consistently reduced leukemic expansion in vivo, and LYN-deficient fibroblasts showed reduced leukemic support in vitro. This indicated a CLL-supportive function for LYN kinase expression in stromal fibroblasts.
A multi-omic characterization of the LYN-deficient fibroblasts revealed an extensive transcriptional reprogramming, affecting predominantly inflammation-, cytokine- and extracellular matrix-related cellular signatures. Combined, these changes indicated a reduced “CAF-like” activation of fibroblasts upon LYN depletion, which could be validated on primary pancreatic cancer specimens.
In particular, the perturbated extracellular matrix deposition was shown to decrease viability in CLL coculture experiments. Specifically, increased THBS1 expression impaired CLL cell viability via ligation to CD47.
Mechanistically, epigenetic analyses identified a reduced c-Jun expression following LYN deficiency, leading to the transcriptional reprogramming with reduced inflammatory signaling and disinhibition of THBS1 expression.
Lastly, we could demonstrate that the stromal reprogramming also affected interaction with other components of the TME: CD4+ and CD8+ T cells cultured in vitro with LYN-deficient fibroblasts showed a reduced activation and modulated exhaustion marker expression, indicating a change in stromal immunomodulatory capacity.

All in all, this works highlights the role of stromal LYN kinase expression for induction of a “CAF-like”, leukemia supportive transcriptional reprogramming in stromal fibroblasts. By regulating transcription factors like c-Jun, LYN kinase governs inflammatory signatures and extracellular matrix deposition in fibroblasts. LYN deficiency reduces c-Jun levels and disinhibits THBS1 expression, inducing CLL cell apoptosis.