Abstract
T cell Acute Lymphoblastic Leukemia/Lymphoma (T-ALL/LBL) is a precursor T cell leukemia/lymphoma that represents approximately 15% of all childhood and 25% of adult acute lymphoblastic leukemia. Although a high cure rate is observed in children, therapy resistance is often observed in adults and mechanisms leading to this resistance remain elusive. Utilizing public gene expression datasets, a fibrotic signature was detected in T-LBL but not T-ALL biopsies. Further, using a T-ALL cell line, CCRF-CEM (CEM) cells, we show that CEM cells induce pulmonary remodeling in immunocompromised mice, suggesting potential interaction between these cells and lung fibroblasts. Co-culture studies suggested that fibroblasts-induced phenotypic and genotypic divergence in co-cultured CEM cells leading to diminished therapeutic responses in vitro. Senescent rather than proliferating stromal cells induced these effects in CEM cells, due, in part, to the enhanced production of oxidative radicals and exosomes containing miRNAs targeting BRCA1 and components of the Mismatch Repair pathway (MMR). Collectively, our studies demonstrate that there may be bidirectional interaction between leukemic cells and stroma, where leukemic cells induce stromal development in vivo and senescent stromal cells generates genomic alterations in the leukemic cells rendering them therapeutic resistant. Thus, targeting senescent stroma might prove beneficial in T-ALL/LBL patients.
Highlights
T cell lymphoblastic lymphoma (T-LBL) is precursor T cell lymphoma that represents the second most common subtype of Non-Hodgkin lymphoma in children and adolescent and is less common in adults
These data suggest that T-ALL and T-LBL might be differentially altered by their micro-environments, and resident stromal cells might exert a prominent role in these alterations
While pediatric T-LBL has a high cure rate of 90% with an intensive multi-agent therapy regiment [24], adult T-LBL remains therapeutically challenging and approximately 40% of adult T-LBL patients relapse with half of those occurring in the mediastinum [11]
Summary
T cell lymphoblastic lymphoma (T-LBL) is precursor T cell lymphoma that represents the second most common subtype of Non-Hodgkin lymphoma in children and adolescent and is less common in adults. T-LBL share many characteristics with the precursor T cell leukemia (T-ALL), which prompted the World Health Organization to unify them as precursor T Cell lymphoblastic leukemia/lymphoma [2]. Despite the similarities between these two entities, T-LBL often presents clinically with a large mediastinal mass and rarely involves the bone marrow, unlike T-ALL, which often involves the bone marrow. Both T-ALL and T-LBL have an 8090% overall 5-year survival rate in children after high-dose multi-agent chemotherapy. Mechanisms leading to T-ALL/LBL relapse and therapy resistance remain elusive
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