Senescent stromal cell-induced divergence and therapeutic resistance in T cell acute lymphoblastic leukemia/lymphoma.
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.
Division of Pulmonary and Critical Care Medicine, Department of Medicine & Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
David M
DM
Habiel
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Nicolas
N
Krepostman
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Michael
M
Lilly
SOCCI Cancer Institute, Urologic Oncology Research Program, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
Karen
K
Cavassani
Division of Pulmonary and Critical Care Medicine, Department of Medicine & Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
Ana Lucia
AL
Coelho
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Takehiko
T
Shibata
Department of Pathology and Laboratory medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, 19104, USA.
Kojo
K
Elenitoba-Johnson
Division of Pulmonary and Critical Care Medicine, Department of Medicine & Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
Cory M
CM
Hogaboam
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000235:genetics; D000072645:Cancer-Associated Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002450:Cell Communication; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D002675:Child, Preschool; D018920:Coculture Techniques; D053843:DNA Mismatch Repair / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D055354:Exosomes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D005838:Genotype; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics; D010641:Phenotype; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D035683:MicroRNAs
T cell acute lymphoblastic leukemia; T cell lymphoblastic lymphoma; cancer microenvironment; oncogenesis; senescent fibroblasts