Stress pathways controlling HNSCC dormancy are differenzially regulated in pediatric ALL cell lines

Introduction: In pediatric ALL, achieving complete remission shortly after therapy initiation isprognostic, but little is known on dormancy of leukemic cells surviving chemotherapy in the bone marrow (BM) niche. InHNSCC, dormancy is maintained by MAPK-dependent regulation of stress pathways in the ER. Mediators of ER-stress orchestrate a cellular response characterized by growth arrest and survival upon chemotherapeutic or microenvironmental stress.

Method: In vitro studies to elucidate mechanisms mediating ALL dormancy in the BM microenvironment.

Results: TEL-AML1 positive REH cells display a dormancy signature characterized by high phosphorylation of p38 and eIF2α. SUP-B15 cells (BCR-ABL1 positive) express low levels of these markers. Upon co-culture with MSC cells, grp78 (a p38-regulated ER-chaperone) is upregulated in REH but not in SUP-B15 cells. This is accompanied by growth arrest and marked resistance to L-Asparaginase. Last, only REH cells are able to splice the ER-stress regulated transcription factor XBP-1 upon stress, a response entirely absent in SUP-B15 cells.

Conclusion: p38 and ER-stress pathways may be connected to growth arrest and therapy resistance of TEL-AML1 positive leukemic cells in the BM microenvironment.