2024
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 drug
HOFERKOVÁ, Eva, Václav ŠEDA, Soňa CESNÁRIKOVÁ, Jan VERNER, Tomáš LOJA et. al.Basic information
Original name
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 drug
Authors
HOFERKOVÁ, Eva (203 Czech Republic, belonging to the institution), Václav ŠEDA (203 Czech Republic, belonging to the institution), Soňa CESNÁRIKOVÁ (703 Slovakia, belonging to the institution), Jan VERNER (203 Czech Republic, belonging to the institution), Tomáš LOJA (703 Slovakia, belonging to the institution), Květoslava MATULOVÁ (203 Czech Republic, belonging to the institution), Hana SKUHROVÁ FRANCOVÁ (203 Czech Republic, belonging to the institution), Eva ONDROUŠKOVÁ (203 Czech Republic, belonging to the institution), Daniel FILIP (703 Slovakia, belonging to the institution), Nicolas BLAVET (250 France, belonging to the institution), Miroslav BOUDNÝ (203 Czech Republic, belonging to the institution), Gabriela MLADONICKÁ PAVLASOVÁ (203 Czech Republic, belonging to the institution), Josef VEČEŘA (203 Czech Republic, belonging to the institution), Laura ONDRIŠOVÁ (703 Slovakia, belonging to the institution), Petra PAVELKOVÁ (203 Czech Republic, belonging to the institution), Kryštof HLAVÁČ (203 Czech Republic, belonging to the institution), Lenka KOŠŤÁLOVÁ (203 Czech Republic, belonging to the institution), Androniki MICHAELOU (196 Cyprus, belonging to the institution), Šárka POSPÍŠILOVÁ (203 Czech Republic, belonging to the institution), Jana DORAZILOVÁ (203 Czech Republic), Václav CHOCHOLA (203 Czech Republic, belonging to the institution), Josef JAROŠ (203 Czech Republic, belonging to the institution), Michael DOUBEK (203 Czech Republic, belonging to the institution), Marie JAROŠOVÁ (203 Czech Republic, belonging to the institution), Aleš HAMPL (203 Czech Republic, belonging to the institution), Lucy VOJTOVÁ (203 Czech Republic), Leoš KŘEN (203 Czech Republic, belonging to the institution), Jiří MAYER (203 Czech Republic, belonging to the institution) and Marek MRÁZ (203 Czech Republic, guarantor, belonging to the institution)
Edition
Leukemia, LONDON, SPRINGERNATURE, 2024, 0887-6924
Other information
Language
English
Type of outcome
Article in a journal
Field of Study
30205 Hematology
Country of publisher
United Kingdom of Great Britain and Northern Ireland
Confidentiality degree
is not subject to a state or trade secret
References:
Impact factor
Impact factor: 12.800 in 2023
RIV identification code
RIV/00216224:14740/24:00136286
Organization unit
Central European Institute of Technology
UT WoS
001247878900001
Keywords in English
stromal cells; T cell factors; CLL cell proliferation
Tags
International impact, Reviewed
Changed: 4/4/2025 16:04, Mgr. Eva Dubská
Abstract
V originále
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.
Links
| LX22NPO5102, research and development project |
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| MUNI/A/1558/2023, interní kód MU |
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| MUNI/A/1598/2023, interní kód MU |
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| NU23-08-00448, research and development project |
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| 802644, interní kód MU |
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| 90267, large research infrastructures |
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