GAB1 Regulates homing capacity and tonic akt activity in chronic lymphocytic leukemia: novel therapeutic target

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F65269705%3A_____%2F21%3A00074817" target="_blank" >RIV/65269705:_____/21:00074817 - isvavai.cz</a>

Výsledek na webu

<a href="https://csbmb2021.cz/wp-content/uploads/2022/01/CBT_Biosjezd-Program-sbornik-2021_1-216str_181-245_press1.pdf" target="_blank" >https://csbmb2021.cz/wp-content/uploads/2022/01/CBT_Biosjezd-Program-sbornik-2021_1-216str_181-245_press1.pdf</a>

DOI - Digital Object Identifier

—

Jazyk výsledku

angličtina

Název v původním jazyce

GAB1 Regulates homing capacity and tonic akt activity in chronic lymphocytic leukemia: novel therapeutic target

Popis výsledku v původním jazyce

CLL cell recirculation between peripheral blood and immune niches plays an important role in CLL biology. However, it remains largely unknown how precisely CLL cells regulate their homing or how they balance survival in peripheral blood and the decision to return to immune niches. To identify novel migration regulators, we have performed transcriptional analysis of CLL cells ready to enter immune niches versus cells that recently exited the immune niches (n=10 pairs). This identified 147 differentially expressed genes that were annotated in databases as migration-related. Among them, we have noticed the overexpression of GAB1 gene (~2 fold). GAB1-attenuation in MEC1 B cells or primary CLL cells largely inhibited their migration capacity towards chemokines like SDF1, CXCL13, or conditioned media produced by bone marrow stromal cells. Importantly, GAB1 knockout or silencing led to clearly impaired migration of malignant B cells to the spleen of NGS mice (P&lt;0.05, n=14). We have also identified another GAB1 function in the maintenance of &quot;tonic&quot; AKT phosphorylation, which contributes to CLL cell survival in peripheral blood especially during ibrutinib therapy, which induces GAB1 expression and compensatory AKT activation (n=11). Recently, novel GAB1 inhibitors were synthesized and we demonstrated that they exhibit potential to inhibit CLL migration, tonic AKT activity, and adaptive AKT activation during ibrutinib therapy.

Název v anglickém jazyce

GAB1 Regulates homing capacity and tonic akt activity in chronic lymphocytic leukemia: novel therapeutic target

Popis výsledku anglicky

CLL cell recirculation between peripheral blood and immune niches plays an important role in CLL biology. However, it remains largely unknown how precisely CLL cells regulate their homing or how they balance survival in peripheral blood and the decision to return to immune niches. To identify novel migration regulators, we have performed transcriptional analysis of CLL cells ready to enter immune niches versus cells that recently exited the immune niches (n=10 pairs). This identified 147 differentially expressed genes that were annotated in databases as migration-related. Among them, we have noticed the overexpression of GAB1 gene (~2 fold). GAB1-attenuation in MEC1 B cells or primary CLL cells largely inhibited their migration capacity towards chemokines like SDF1, CXCL13, or conditioned media produced by bone marrow stromal cells. Importantly, GAB1 knockout or silencing led to clearly impaired migration of malignant B cells to the spleen of NGS mice (P&lt;0.05, n=14). We have also identified another GAB1 function in the maintenance of &quot;tonic&quot; AKT phosphorylation, which contributes to CLL cell survival in peripheral blood especially during ibrutinib therapy, which induces GAB1 expression and compensatory AKT activation (n=11). Recently, novel GAB1 inhibitors were synthesized and we demonstrated that they exhibit potential to inhibit CLL migration, tonic AKT activity, and adaptive AKT activation during ibrutinib therapy.

Druh

O - Ostatní výsledky

CEP obor

—

OECD FORD obor

30204 - Oncology

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

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2021

Kód důvěrnosti údajů

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