STROMAL CELLS ENGINEERED TO EXPRESS T CELL FACTORS INDUCE ROBUST CLL CELL PROLIFERATION IN VITRO AND IN PDX COTRANSPLANTATIONS ALLOWING THE IDENTIFICATION OF ANTI-PROLIFERATIVE DRUGS

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14740%2F24%3A00137865" target="_blank" >RIV/00216224:14740/24:00137865 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.hematology2024.cz/" target="_blank" >https://www.hematology2024.cz/</a>

DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

STROMAL CELLS ENGINEERED TO EXPRESS T CELL FACTORS INDUCE ROBUST CLL CELL PROLIFERATION IN VITRO AND IN PDX COTRANSPLANTATIONS ALLOWING THE IDENTIFICATION OF ANTI-PROLIFERATIVE DRUGS

Popis výsledku v původním jazyce

Several in vitro models have been developed to mimic CLL proliferation in immune niches; however, they typically do not induce robust proliferation. We prepared a novel model based on mimicking T-cell signals. 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 led to mild CLL cell proliferation (median 7% at day 7), while the HS5 expressing CD40L, IL4, and IL21 led to unprecedented proliferation rate of 44%, which is higher and more reproducible then in other available models. The co-cultures mimicked the gene expression fingerprint of lymph node CLL cells (MYC, NFkB, and E2F signatures; as defined by Herishanu et al, 2011). The other induced pathways reveal novel CLL vulnerabilities in context of CLL-T cell-induced proliferation, and we tested 10 inhibitors based on these data. This revealed for the first time that RAF inhibitors and FOXO1 inhibitors 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. We co-transplanted 41 NSG mice with CLL cells and HS5-CD40L-IL4 or HS5-CD40L-IL4-IL21 using a subcutaneous scaffold and intraperitoneal injection leading to 47% or 82% engraftment efficacy, respectively, with ~20% of PDXs being clonally related to CLL. This shows that CLL cell engraftment in NSG mice can be supported by engineered HS5 cells, thus bypassing the need to use primary T cells in PDX (Bagnara et al, 2011).

Název v anglickém jazyce

STROMAL CELLS ENGINEERED TO EXPRESS T CELL FACTORS INDUCE ROBUST CLL CELL PROLIFERATION IN VITRO AND IN PDX COTRANSPLANTATIONS ALLOWING THE IDENTIFICATION OF ANTI-PROLIFERATIVE DRUGS

Popis výsledku anglicky

Several in vitro models have been developed to mimic CLL proliferation in immune niches; however, they typically do not induce robust proliferation. We prepared a novel model based on mimicking T-cell signals. 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 led to mild CLL cell proliferation (median 7% at day 7), while the HS5 expressing CD40L, IL4, and IL21 led to unprecedented proliferation rate of 44%, which is higher and more reproducible then in other available models. The co-cultures mimicked the gene expression fingerprint of lymph node CLL cells (MYC, NFkB, and E2F signatures; as defined by Herishanu et al, 2011). The other induced pathways reveal novel CLL vulnerabilities in context of CLL-T cell-induced proliferation, and we tested 10 inhibitors based on these data. This revealed for the first time that RAF inhibitors and FOXO1 inhibitors 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. We co-transplanted 41 NSG mice with CLL cells and HS5-CD40L-IL4 or HS5-CD40L-IL4-IL21 using a subcutaneous scaffold and intraperitoneal injection leading to 47% or 82% engraftment efficacy, respectively, with ~20% of PDXs being clonally related to CLL. This shows that CLL cell engraftment in NSG mice can be supported by engineered HS5 cells, thus bypassing the need to use primary T cells in PDX (Bagnara et al, 2011).

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

30204 - Oncology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů