Senescent stromal cell-induced divergence and therapeutic resistance in T cell acute lymphoblastic leukemia/lymphoma
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David M. Habiel1, Nicolas Krepostman2, Michael Lilly2, Karen Cavassani3, Ana Lucia Coelho1, Takehiko Shibata2, Kojo Elenitoba-Johnson4, Cory M. Hogaboam1
1Division of Pulmonary and Critical Care Medicine, Department of Medicine & Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
2Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109–2200, USA
3SOCCI Cancer Institute, Urologic Oncology Research Program, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
4Department of Pathology and Laboratory medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, 19104, USA
David M. Habiel, email: David.Habiel@cshs.org
Keywords: T cell acute lymphoblastic leukemia, senescent fibroblasts, T cell lymphoblastic lymphoma, oncogenesis, cancer microenvironment
Received: August 17, 2016 Accepted: October 13, 2016 Published: November 7, 2016
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.
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