Back to Search
Start Over
Stromal cells engineered to express T cell factors induce robust CLL cell proliferation in vitro and in PDX co-transplantations allowing the identification of RAF inhibitors as anti-proliferative drugs.
- Source :
-
Leukemia [Leukemia] 2024 Aug; Vol. 38 (8), pp. 1699-1711. Date of Electronic Publication: 2024 Jun 14. - Publication Year :
- 2024
-
Abstract
- Several in vitro models have been developed to mimic chronic lymphocytic leukemia (CLL) proliferation in immune niches; however, they typically do not induce robust proliferation. We prepared a novel model based on mimicking T-cell signals in vitro and in patient-derived xenografts (PDXs). Six supportive cell lines were prepared by engineering HS5 stromal cells with stable expression of human CD40L, IL4, IL21, and their combinations. Co-culture with HS5 expressing CD40L and IL4 in combination led to mild CLL cell proliferation (median 7% at day 7), while the HS5 expressing CD40L, IL4, and IL21 led to unprecedented proliferation rate (median 44%). The co-cultures mimicked the gene expression fingerprint of lymph node CLL cells (MYC, NFκB, and E2F signatures) and revealed novel vulnerabilities in CLL-T-cell-induced proliferation. Drug testing in co-cultures revealed for the first time that pan-RAF inhibitors fully block CLL proliferation. The co-culture model can be downscaled to five microliter volume for large drug screening purposes or upscaled to CLL PDXs by HS5-CD40L-IL4 ± IL21 co-transplantation. Co-transplanting NSG mice with purified CLL cells and HS5-CD40L-IL4 or HS5-CD40L-IL4-IL21 cells on collagen-based scaffold led to 47% or 82% engraftment efficacy, respectively, with ~20% of PDXs being clonally related to CLL, potentially overcoming the need to co-transplant autologous T-cells in PDXs.<br /> (© 2024. The Author(s).)
- Subjects :
- Humans
Animals
Mice
T-Lymphocytes immunology
T-Lymphocytes metabolism
Xenograft Model Antitumor Assays
Interleukins genetics
Interleukins metabolism
Protein Kinase Inhibitors pharmacology
Leukemia, Lymphocytic, Chronic, B-Cell pathology
Leukemia, Lymphocytic, Chronic, B-Cell genetics
Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
Cell Proliferation
Coculture Techniques
Stromal Cells metabolism
Stromal Cells pathology
CD40 Ligand metabolism
CD40 Ligand genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5551
- Volume :
- 38
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Leukemia
- Publication Type :
- Academic Journal
- Accession number :
- 38877102
- Full Text :
- https://doi.org/10.1038/s41375-024-02284-w