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

Result code in 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>

Result on the web

<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

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Result language

angličtina

Original language name

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

Original language description

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.

Czech name

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Czech description

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Type

O - Miscellaneous

CEP classification

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OECD FORD branch

30204 - Oncology

Project

<a href="/en/project/GA20-02566S" target="_blank" >GA20-02566S: FOXO1-GAB1 AXIS AND MOLECULAR PATHWAYS GUIDING RE-CIRCULATION OF LEUKEMIC B CELLS TO IMMUNE NICHES: THERAPEUTIC IMPLICATIONS</a><br>

Continuities

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

Publication year

2021

Confidentiality

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