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

The Journal of Clinical Investigation
Marina García-PeydróMaría L Toribio

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 ant...Continue Reading

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Citations

Oct 19, 2019·Cancers·Beatriz P San JuanChristine L Chaffer
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Datasets Mentioned

BETA
GSE51800

Methods Mentioned

BETA
xenografts
FACS
ChIP
flow cytometry
xenograft
FCS
PCR

Software Mentioned

ELDA
MULAN

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