Hypermethylation of CD19 promoter enables antigen-negative
escape to CART-19 in vivo and in vitro

J 2021

Hypermethylation of CD19 promoter enables antigen-negative escape to CART-19 in vivo and in vitro

LEDEREROVÁ, Aneta; Lenka DOSTÁLOVÁ; Veronika KOZLOVÁ; Helena PESCHELOVÁ; Adriana LADUNGOVÁ et. al.

Základní údaje

Originální název

Hypermethylation of CD19 promoter enables antigen-negative escape to CART-19 in vivo and in vitro

Autoři

Vydání

Journal for ImmunoTherapy of Cancer, Switzerland, Springer International Publishing AG, 2021, 2051-1426

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30204 Oncology

Stát vydavatele

Velká Británie a Severní Irsko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 12.485

Kód RIV

RIV/00216224:14740/21:00119907

Organizační jednotka

Středoevropský technologický institut

DOI

https://doi.org/10.1136/jitc-2021-002352

UT WoS

000687297900004

EID Scopus

2-s2.0-85113641819

Klíčová slova anglicky

antigens; B-lymphocytes; hematologic neoplasms; receptors; chimeric antigen; translational medical research

Štítky

14110212, 14110513, CF GEN, EATRIS, podil, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 4. 11. 2025 09:59, Mgr. Eva Dubská

Anotace

V originále

Background Anti-CD19 chimeric antigen receptor T cells (CART-19) frequently induce remissions in hemato-oncological patients with recurred and/or refractory B-cell tumors. However, malignant cells sometimes escape the immunotherapeutic targeting by CD19 gene mutations, alternative splicing or lineage switch, commonly causing lack of CD19 expression on the surface of neoplastic cells. We assumed that, in addition to the known mechanisms, other means could act on CD19 to drive antigen-negative relapse. Methods Herein, we studied the mechanism of antigen loss in an in vivo CD19-negative recurrence model of chronic lymphocytic leukemia (CLL) to CART-19, established using NOD-scid IL2Rg(null) mice and HG3 cell line. We validated our findings in vitro in immortalized B-cell lines and primary CLL cells. Results In our in vivo CLL recurrence model, up to 70% of CART-19-treated mice eventually recurred with CD19-negative disease weeks after initial positive response. We found that the lack of CD19 expression was caused by promoter DNA hypermethylation. Importantly, the expression loss was partially reversible by treatment with a demethylating agent. Moreover, this escape mechanism was common for 3 B-cell immortalized lines as well as primary CLL cells, as assessed by in vitro coculture experiments. Conclusions Epigenetically driven antigen escape could represent a novel, yet at least partially reversible, means of CD19 loss to CART-19 in B-cell tumors.

Návaznosti

EF18_046/0015515, projekt VaV

Název: Modernizace a rozšíření přístrojového vybavení Národního centra lékařské genomiky

MUNI/A/1595/2020, interní kód MU

Název: Nové přístupy ve výzkumu, diagnostice a terapii hematologických malignit VIII (Akronym: VýDiTeHeMa VIII)

Investor: Masarykova univerzita, Nové přístupy ve výzkumu, diagnostice a terapii hematologických malignit VIII

TN01000013, projekt VaV

Název: Personalizovaná medicína - diagnostika a terapie

Investor: Technologická agentura ČR, Personalizovaná medicína - diagnostika a terapie

90132, velká výzkumná infrastruktura

Název: NCMG II

90133, velká výzkumná infrastruktura

Název: EATRIS-CZ III

Citovat

LEDEREROVÁ, Aneta; Lenka DOSTÁLOVÁ; Veronika KOZLOVÁ; Helena PESCHELOVÁ; Adriana LADUNGOVÁ; Martin ČULEN; Tomáš LOJA; Jan VERNER; Šárka POSPÍŠILOVÁ; Michal ŠMÍDA a Veronika MANČÍKOVÁ. Hypermethylation of CD19 promoter enables antigen-negative escape to CART-19 in vivo and in vitro. Journal for ImmunoTherapy of Cancer. Switzerland: Springer International Publishing AG, 2021, roč. 9, č. 8, s. 1-8. ISSN 2051-1426. Dostupné z: https://doi.org/10.1136/jitc-2021-002352.

@article{1813004,
   author = {Ledererová, Aneta and Dostálová, Lenka and Kozlová, Veronika and Peschelová, Helena and Ladungová, Adriana and Čulen, Martin and Loja, Tomáš and Verner, Jan and Pospíšilová, Šárka and Šmída, Michal and Mančíková, Veronika},
   article_location = {Switzerland},
   article_number = {8},
   doi = {https://doi.org/10.1136/jitc-2021-002352},
   keywords = {antigens; B-lymphocytes; hematologic neoplasms; receptors; chimeric antigen; translational medical research},
   language = {eng},
   issn = {2051-1426},
   journal = {Journal for ImmunoTherapy of Cancer},
   title = {Hypermethylation of CD19 promoter enables antigen-negative escape to CART-19 in vivo and in vitro},
   url = {https://jitc.bmj.com/content/9/8/e002352},
   volume = {9},
   year = {2021}
}

TY  - JOUR
ID  - 1813004
AU  - Ledererová, Aneta - Dostálová, Lenka - Kozlová, Veronika - Peschelová, Helena - Ladungová, Adriana - Čulen, Martin - Loja, Tomáš - Verner, Jan - Pospíšilová, Šárka - Šmída, Michal - Mančíková, Veronika
PY  - 2021
TI  - Hypermethylation of CD19 promoter enables antigen-negative escape to CART-19 in vivo and in vitro
JF  - Journal for ImmunoTherapy of Cancer
VL  - 9
IS  - 8
SP  - 1-8
EP  - 1-8
PB  - Springer International Publishing AG
SN  - 20511426
KW  - antigens
KW  - B-lymphocytes
KW  - hematologic neoplasms
KW  - receptors
KW  - chimeric antigen
KW  - translational medical research
UR  - https://jitc.bmj.com/content/9/8/e002352
N2  - Background Anti-CD19 chimeric antigen receptor T cells (CART-19) frequently induce remissions in hemato-oncological patients with recurred and/or refractory B-cell tumors. However, malignant cells sometimes escape the immunotherapeutic targeting by CD19 gene mutations, alternative splicing or lineage switch, commonly causing lack of CD19 expression on the surface of neoplastic cells. We assumed that, in addition to the known mechanisms, other means could act on CD19 to drive antigen-negative relapse. Methods Herein, we studied the mechanism of antigen loss in an in vivo CD19-negative recurrence model of chronic lymphocytic leukemia (CLL) to CART-19, established using NOD-scid IL2Rg(null) mice and HG3 cell line. We validated our findings in vitro in immortalized B-cell lines and primary CLL cells. Results In our in vivo CLL recurrence model, up to 70% of CART-19-treated mice eventually recurred with CD19-negative disease weeks after initial positive response. We found that the lack of CD19 expression was caused by promoter DNA hypermethylation. Importantly, the expression loss was partially reversible by treatment with a demethylating agent. Moreover, this escape mechanism was common for 3 B-cell immortalized lines as well as primary CLL cells, as assessed by in vitro coculture experiments. Conclusions Epigenetically driven antigen escape could represent a novel, yet at least partially reversible, means of CD19 loss to CART-19 in B-cell tumors.
ER  -

LEDEREROVÁ, Aneta; Lenka DOSTÁLOVÁ; Veronika KOZLOVÁ; Helena PESCHELOVÁ; Adriana LADUNGOVÁ; Martin ČULEN; Tomáš LOJA; Jan VERNER; Šárka POSPÍŠILOVÁ; Michal ŠMÍDA a Veronika MANČÍKOVÁ. Hypermethylation of CD19 promoter enables antigen-negative escape to CART-19 in vivo and in vitro. \textit{Journal for ImmunoTherapy of Cancer}. Switzerland: Springer International Publishing AG, 2021, roč.~9, č.~8, s.~1-8. ISSN~2051-1426. Dostupné z: https://doi.org/10.1136/jitc-2021-002352.

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