Publication detail

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

HOFERKOVA, E. SEDA, V. KADAKOVA, S. VERNER, J. LOJA, T. MATULOVA, K. FRANCOVA, HS. ONDROUSKOVA, E. FILIP, D. BLAVET, N. BOUDNY, M. PAVLASOVA, GM. VECERA, J. ONDRISOVA, L. PAVELKOVA, P. HLAVAC, K. KOSTALOVA, L. MICHAELOU, A. POSPISILOVA, S. DORAZILOVA, J. CHOCHOLA, V. JAROS, J. DOUBEK, M. JAROSOVA, M. HAMPL, A. VOJTOVA, L. KREN, L. MAYER, J. MRAZ, M

Original Title

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

Type

journal article in Web of Science

Language

English

Original 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, NF kappa B, 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 similar to 20% of PDXs being clonally related to CLL, potentially overcoming the need to co-transplant autologous T-cells in PDXs.

Keywords

chronic-lymphocytic-leukemia, antigen-independent proliferation; bone-marrow; induced apoptosis; up-regulation; B-cells; lymphoma; receptor; activation

Authors

HOFERKOVA, E.; SEDA, V.; KADAKOVA, S.; VERNER, J.; LOJA, T.; MATULOVA, K.; FRANCOVA, HS.; ONDROUSKOVA, E.; FILIP, D.; BLAVET, N.; BOUDNY, M.; PAVLASOVA, GM.; VECERA, J.; ONDRISOVA, L.; PAVELKOVA, P.; HLAVAC, K.; KOSTALOVA, L.; MICHAELOU, A.; POSPISILOVA, S.; DORAZILOVA, J.; CHOCHOLA, V.; JAROS, J. ; DOUBEK, M.; JAROSOVA, M.; HAMPL, A.; VOJTOVA, L.; KREN, L. ; MAYER, J.; MRAZ, M

Released

14. 6. 2024

Publisher

SPRINGERNATURE

Location

LONDON

ISBN

1476-5551

Periodical

Leukemia

Year of study

38

Number

8

State

United Kingdom of Great Britain and Northern Ireland

Pages from

1699

Pages to

1711

Pages count

13

URL

https://www.nature.com/articles/s41375-024-02284-w

BibTex

@article{BUT190008,
  author="HOFERKOVA, E. and SEDA, V. and KADAKOVA, S. and VERNER, J. and LOJA, T. and MATULOVA, K. and FRANCOVA, HS. and ONDROUSKOVA, E. and FILIP, D. and BLAVET, N. and BOUDNY, M. and PAVLASOVA, GM. and VECERA, J. and ONDRISOVA, L. and PAVELKOVA, P. and HLAVAC, K. and KOSTALOVA, L. and MICHAELOU, A. and POSPISILOVA, S. and DORAZILOVA, J. and CHOCHOLA, V. and JAROS, J. and DOUBEK, M. and JAROSOVA, M. and HAMPL, A. and VOJTOVA, L. and KREN, L. and MAYER, J. and MRAZ, M",
  title="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",
  journal="Leukemia",
  year="2024",
  volume="38",
  number="8",
  pages="1699--1711",
  doi="10.1038/s41375-024-02284-w",
  issn="1476-5551",
  url="https://www.nature.com/articles/s41375-024-02284-w"
}