High surface IgM levels associate with shorter response to ibrutinib and BTK bypass in patients with CLL

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14740%2F22%3A00127431" target="_blank" >RIV/00216224:14740/22:00127431 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/65269705:_____/22:00076462

Výsledek na webu

<a href="https://ashpublications.org/bloodadvances/article/6/18/5494/485430/High-surface-IgM-levels-associate-with-shorter" target="_blank" >https://ashpublications.org/bloodadvances/article/6/18/5494/485430/High-surface-IgM-levels-associate-with-shorter</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1182/bloodadvances.2021006659" target="_blank" >10.1182/bloodadvances.2021006659</a>

Jazyk výsledku

angličtina

Název v původním jazyce

High surface IgM levels associate with shorter response to ibrutinib and BTK bypass in patients with CLL

Popis výsledku v původním jazyce

Chronic lymphocytic leukemia (CLL) cells have variably low surface IgM (sIgM) levels/ signaling capacity, influenced by chronic antigen engagement at tissue sites. Within these low levels, CLL with relatively high sIgM (CLLhigh) progresses more rapidly than CLL with low sIgM (CLLlow). During ibrutinib therapy, surviving CLL cells redistribute into the peripheral blood and can recover sIgM expression. Return of CLL cells to tissue may eventually recur, where cells with high sIgM could promote tumor growth. We analyzed time to new treatment (TTNT) following ibrutinib in 70 patients with CLL (median follow-up of 66 months) and correlated it with pretreatment sIgM levels and signaling characteristics. Pretreatment sIgM levels correlated with signaling capacity, as measured by intracellular Ca2+ mobilization (iCa2+), in vitro (r = 0.70; P &lt; .0001). High sIgM levels/ signaling strongly correlated with short TTNT (P &lt; .05), and 36% of patients with CLLhigh vs 8% of patients with CLLlow progressed to require a new treatment. In vitro, capacity of ibrutinib to inhibit sIgM-mediated signaling inversely correlated with pretherapy sIgM levels (r = -0.68; P = .01) or iCa2+ (r = -0.71; P = .009). In patients, sIgM-mediated iCa2+ and ERK phosphorylation levels were reduced by ibrutinib therapy but not abolished. The residual signaling capacity downstream of BTK was associated with high expression of sIgM, whereas it was minimal when sIgM expression was low (P &lt; .05). These results suggested that high sIgM levels facilitated CLL cell resistance to ibrutinib in patients. The CLL cells, surviving in the periphery with high sIgM expression, include a dangerous fraction that is able to migrate to tissue and receive proliferative stimuli, which may require targeting by combined approaches.

Název v anglickém jazyce

High surface IgM levels associate with shorter response to ibrutinib and BTK bypass in patients with CLL

Popis výsledku anglicky

Chronic lymphocytic leukemia (CLL) cells have variably low surface IgM (sIgM) levels/ signaling capacity, influenced by chronic antigen engagement at tissue sites. Within these low levels, CLL with relatively high sIgM (CLLhigh) progresses more rapidly than CLL with low sIgM (CLLlow). During ibrutinib therapy, surviving CLL cells redistribute into the peripheral blood and can recover sIgM expression. Return of CLL cells to tissue may eventually recur, where cells with high sIgM could promote tumor growth. We analyzed time to new treatment (TTNT) following ibrutinib in 70 patients with CLL (median follow-up of 66 months) and correlated it with pretreatment sIgM levels and signaling characteristics. Pretreatment sIgM levels correlated with signaling capacity, as measured by intracellular Ca2+ mobilization (iCa2+), in vitro (r = 0.70; P &lt; .0001). High sIgM levels/ signaling strongly correlated with short TTNT (P &lt; .05), and 36% of patients with CLLhigh vs 8% of patients with CLLlow progressed to require a new treatment. In vitro, capacity of ibrutinib to inhibit sIgM-mediated signaling inversely correlated with pretherapy sIgM levels (r = -0.68; P = .01) or iCa2+ (r = -0.71; P = .009). In patients, sIgM-mediated iCa2+ and ERK phosphorylation levels were reduced by ibrutinib therapy but not abolished. The residual signaling capacity downstream of BTK was associated with high expression of sIgM, whereas it was minimal when sIgM expression was low (P &lt; .05). These results suggested that high sIgM levels facilitated CLL cell resistance to ibrutinib in patients. The CLL cells, surviving in the periphery with high sIgM expression, include a dangerous fraction that is able to migrate to tissue and receive proliferative stimuli, which may require targeting by combined approaches.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30205 - Hematology

Projekt

<a href="/cs/project/GA20-02566S" target="_blank" >GA20-02566S: FOXO1-GAB1 SIGNALIZACE A MOLEKULÁRNÍ DRÁHY ŘÍDÍCI RE-CIRKULACI LEUKEMICKÝCH B BUNĚK DO IMUNITNÍCH NICHE: TERAPEUTICKÉ IMPLIKACE</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2022

Kód důvěrnosti údajů

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

Název periodika

BLOOD ADVANCES

ISSN

2473-9529

e-ISSN

—

Svazek periodika

6

Číslo periodika v rámci svazku

18

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

11

Strana od-do

5494-5504

Kód UT WoS článku

000874686400027

EID výsledku v databázi Scopus

2-s2.0-85139452397