FoxO1-GAB1 axis regulates homing capacity and tonic AKT activity in chronic lymphocytic leukemia

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F65269705%3A_____%2F21%3A00074595" target="_blank" >RIV/65269705:_____/21:00074595 - isvavai.cz</a>

Alternative codes found

RIV/00216305:26620/21:PU141851 RIV/00216224:14740/21:00123376

Result on the web

<a href="https://ashpublications.org/blood/article/138/9/758/475649/FoxO1-GAB1-axis-regulates-homing-capacity-and" target="_blank" >https://ashpublications.org/blood/article/138/9/758/475649/FoxO1-GAB1-axis-regulates-homing-capacity-and</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1182/blood.2020008101" target="_blank" >10.1182/blood.2020008101</a>

Result language

angličtina

Original language name

FoxO1-GAB1 axis regulates homing capacity and tonic AKT activity in chronic lymphocytic leukemia

Original language description

Recirculation of chronic lymphocytic leukemia (CLL) cells between the peripheral blood and lymphoid niches plays a critical role in disease pathophysiology, and inhibiting this process is one of the major mechanisms of action for B-cell receptor (BCR) inhibitors such as ibrutinib and idelalisib. Migration is a complex process guided by chemokine receptors and integrins. However, it remains largely unknown how CLL cells integrate multiple migratory signals while balancing survival in the peripheral blood and the decision to return to immune niches. Our study provided evidence that CXCR4/CD5 intraclonal subpopulations can be used to study the regulation of migration of CLL cells. We performed RNA profiling of CXCR4(dim)CD5(bright) vs CXCR4(bright) CD5(dim) CLL cells and identified differential expression of dozens of molecules with a putative function in cell migration. GRB2-associated binding protein 1 (GAB1) positively regulated CLL cell homing capacity of CXCR4(bright)DD5(dim) cells. Gradual GAB1 accumulation in CLL cells outside immune niches was mediated by FoxO1-induced transcriptional GAB1 activation. Upregulation of GAB1 also played an important role in maintaining basal phosphatidylinositol 3-kinase (P13K) activity and the &quot;tonic&quot; AKT phosphorylation required to sustain the survival of resting CLL B cells. This finding is important during ibrutinib therapy, because CLL cells induce the FoxO1-GAB1-pAKT axis, which represents an adaptation mechanism to the inability to home to immune niches. We have demonstrated that GAB1 can be targeted therapeutically by novel GAB1 inhibitors, alone or in combination with BTK inhibition. GAB1 inhibitors induce CLL cell apoptosis, impair cell migration, inhibit tonic or BCR-induced AKT phosphorylation, and block compensatory AKT activity during ibrutinib therapy.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30205 - Hematology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

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

Name of the periodical

Blood

ISSN

0006-4971

e-ISSN

—

Volume of the periodical

138

Issue of the periodical within the volume

9

Country of publishing house

US - UNITED STATES

Number of pages

15

Pages from-to

758-772

UT code for WoS article

000692441100006

EID of the result in the Scopus database

2-s2.0-85113306446