Dataset Information


The NOTCH1/CD44 axis drives pathogenesis in a T cell acute lymphoblastic leukemia model.

ABSTRACT: NOTCH1 is a prevalent signaling pathway in T cell acute lymphoblastic leukemia (T-ALL), but crucial NOTCH1 downstream signals and target genes contributing to T-ALL pathogenesis cannot be retrospectively analyzed in patients and thus remain ill defined. This information is clinically relevant, as initiating lesions that lead to cell transformation and leukemia-initiating cell (LIC) activity are promising therapeutic targets against the major hurdle of T-ALL relapse. Here, we describe the generation in vivo of a human T cell leukemia that recapitulates T-ALL in patients, which arises de novo in immunodeficient mice reconstituted with human hematopoietic progenitors ectopically expressing active NOTCH1. This T-ALL model allowed us to identify CD44 as a direct NOTCH1 transcriptional target and to recognize CD44 overexpression as an early hallmark of preleukemic cells that engraft the BM and finally develop a clonal transplantable T-ALL that infiltrates lymphoid organs and brain. Notably, CD44 is shown to support crucial BM niche interactions necessary for LIC activity of human T-ALL xenografts and disease progression, highlighting the importance of the NOTCH1/CD44 axis in T-ALL pathogenesis. The observed therapeutic benefit of anti-CD44 antibody administration in xenotransplanted mice holds great promise for therapeutic purposes against T-ALL relapse.

SUBMITTER: Garcia-Peydro M 

PROVIDER: S-EPMC6025994 | BioStudies | 2018-01-01

REPOSITORIES: biostudies

Similar Datasets

1000-01-01 | S-EPMC3156046 | BioStudies
2019-01-01 | S-EPMC6933515 | BioStudies
2012-01-01 | S-EPMC3387267 | BioStudies
1000-01-01 | S-EPMC3924926 | BioStudies
2012-01-01 | S-EPMC3738873 | BioStudies
2017-01-01 | S-EPMC5540588 | BioStudies
2014-01-01 | S-EPMC4258248 | BioStudies
2018-01-01 | S-EPMC5919829 | BioStudies
1000-01-01 | S-EPMC3689964 | BioStudies
2011-01-01 | S-EPMC3171095 | BioStudies