The regulation and function of CD20: an "enigma" of B-cell biology and targeted therapy

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14740%2F20%3A00115840" target="_blank" >RIV/00216224:14740/20:00115840 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/65269705:_____/20:00072781

Výsledek na webu

<a href="http://www.haematologica.org/content/haematol/105/6/1494.full.pdf" target="_blank" >http://www.haematologica.org/content/haematol/105/6/1494.full.pdf</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3324/haematol.2019.243543" target="_blank" >10.3324/haematol.2019.243543</a>

Jazyk výsledku

angličtina

Název v původním jazyce

The regulation and function of CD20: an "enigma" of B-cell biology and targeted therapy

Popis výsledku v původním jazyce

The introduction of anti-CD20 monoclonal antibodies such as rituximab, ofatumumab, or obinutuzumab improved the therapy of Bcell malignancies even though the precise physiological role and regulation of CD20 remains unclear. Furthermore, CD20 expression is highly variable between different B-cell malignancies, patients with the same malignancy, and even between intraclonal subpopulations in an individual patient. Several epigenetic (EZH2, HDAC1/2, HDAC1/4, HDAC6, complex Sin3A-HDAC1) and transcription factors ( USF, OCT1/2, PU.1, PiP, ELK1, ETS1, SP1, NF.B, FOXO1, CREM, SMAD2/3) regulating CD20 expression (encoded by MS4A1) have been characterized. CD20 is induced in the context of microenvironmental interactions by CXCR4/SDF1 (CXCL12) chemokine signaling and the molecular function of CD20 has been linked to the signaling propensity of B-cell receptor (BCR). CD20 has also been shown to interact with multiple other surface proteins on B cells (such as CD40, MHCII, CD53, CD81, CD82, and CBP). Current efforts to combine anti-CD20 monoclonal antibodies with BCR signaling inhibitors targeting BTK or PI3K (ibrutinib, acalabrutinib, idelalisib, duvelisib) or BH3-mimetics (venetoclax) lead to the necessity to better understand both the mechanisms of regulation and the biological functions of CD20. This is underscored by the observation that CD20 is decreased in response to the "BCR inhibitor" ibrutinib which largely prevents its successful combination with rituximab. Several small molecules ( such as histone deacetylase inhibitors, DNA methyl-transferase inhibitors, aurora kinase A/B inhibitors, farnesyltransferase inhibitors, FOXO1 inhibitors, and bryostatin-1) are being tested to upregulate cellsurface CD20 levels and increase the efficacy of anti-CD20 monoclonal antibodies. Herein, we review the current understanding of CD20 function, and the mechanisms of its regulation in normal and malignant B cells, highlighting the therapeutic implications.

Název v anglickém jazyce

The regulation and function of CD20: an "enigma" of B-cell biology and targeted therapy

Popis výsledku anglicky

The introduction of anti-CD20 monoclonal antibodies such as rituximab, ofatumumab, or obinutuzumab improved the therapy of Bcell malignancies even though the precise physiological role and regulation of CD20 remains unclear. Furthermore, CD20 expression is highly variable between different B-cell malignancies, patients with the same malignancy, and even between intraclonal subpopulations in an individual patient. Several epigenetic (EZH2, HDAC1/2, HDAC1/4, HDAC6, complex Sin3A-HDAC1) and transcription factors ( USF, OCT1/2, PU.1, PiP, ELK1, ETS1, SP1, NF.B, FOXO1, CREM, SMAD2/3) regulating CD20 expression (encoded by MS4A1) have been characterized. CD20 is induced in the context of microenvironmental interactions by CXCR4/SDF1 (CXCL12) chemokine signaling and the molecular function of CD20 has been linked to the signaling propensity of B-cell receptor (BCR). CD20 has also been shown to interact with multiple other surface proteins on B cells (such as CD40, MHCII, CD53, CD81, CD82, and CBP). Current efforts to combine anti-CD20 monoclonal antibodies with BCR signaling inhibitors targeting BTK or PI3K (ibrutinib, acalabrutinib, idelalisib, duvelisib) or BH3-mimetics (venetoclax) lead to the necessity to better understand both the mechanisms of regulation and the biological functions of CD20. This is underscored by the observation that CD20 is decreased in response to the "BCR inhibitor" ibrutinib which largely prevents its successful combination with rituximab. Several small molecules ( such as histone deacetylase inhibitors, DNA methyl-transferase inhibitors, aurora kinase A/B inhibitors, farnesyltransferase inhibitors, FOXO1 inhibitors, and bryostatin-1) are being tested to upregulate cellsurface CD20 levels and increase the efficacy of anti-CD20 monoclonal antibodies. Herein, we review the current understanding of CD20 function, and the mechanisms of its regulation in normal and malignant B cells, highlighting the therapeutic implications.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30205 - Hematology

Projekt

<a href="/cs/project/NU20-03-00292" target="_blank" >NU20-03-00292: PRIORITIZACE KOMBINACÍ LÉČIV U CHRONICKÉ LYMFOCYTÁRNÍ LEUKÉMIE NA ZÁKLADĚ ANALÝZY ADAPTACE BUNĚK NA IBRUTINIB A IDELALISIB IN VIVO</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2020

Kód důvěrnosti údajů

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

Název periodika

haematologica

ISSN

0390-6078

e-ISSN

—

Svazek periodika

105

Číslo periodika v rámci svazku

6

Stát vydavatele periodika

IT - Italská republika

Počet stran výsledku

13

Strana od-do

1494-1506

Kód UT WoS článku

000537771300024

EID výsledku v databázi Scopus

2-s2.0-85085880945