TY - JOUR
T1 - FoxO1-GAB1 axis regulates homing capacity and tonic AKT activity in chronic lymphocytic leukemia
AU - Seda, Vaclav
AU - Vojackova, Eva
AU - Ondrisova, Laura
AU - Kostalova, Lenka
AU - Sharma, Sonali
AU - Loja, Tomas
AU - Mladonicka Pavlasova, Gabriela
AU - Zicha, Daniel
AU - Kudlickova Peskova, Marie
AU - Krivanek, Jan
AU - Liskova, Kvetoslava
AU - Kren, Leos
AU - Benes, Vladimir
AU - Musilova Litzmanova, Katerina
AU - Borsky, Marek
AU - Oppelt, Jan
AU - Verner, Jan
AU - Pospisilova, Sarka
AU - Brychtova, Yvona
AU - Panovska, Anna
AU - Tan, Zhi
AU - Zhang, Shuxing
AU - Doubek, Michael
AU - Amruz Cerna, Katerina
AU - Mayer, Jiri
AU - Mraz, Marek
N1 - Funding Information:
The authors thank Zuzana Smrckova (University of Technology, Brno, Czech Republic) for help with cell motility assays. This work was supported by the Czech Science Foundation (project no. 20-02566S). This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (grant agreement no. 802644). This work was supported by the Ministry of Health of the Czech Republic, grant no. NU20-03-00292. All rights reserved. This work was also supported by MH CZ-DRO (FNBr, 65269705) and MUNI/A/1595/2020. The authors acknowledge the CF Genomics CEITEC MU supported by the National Center for Medical Genomics (NCMG) research infrastructure (LM22018132 funded by MEYS CR) and Core Facility Bioinformatics of CEITEC MU for their support in processing the data. This work was supported by the MEYS CR (Large RI Project LM2018129 Czech-BioImaging).
Funding Information:
This work was supported by the Czech Science Foundation (project no. 20-02566S). This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (grant agreement no. 802644). This work was supported by the Ministry of Health of the Czech Republic, grant no. NU20-03-00292. All rights reserved. This work was also supported by MH CZ-DRO (FNBr, 65269705) and MUNI/A/1595/2020. The authors acknowledge the CF Genomics CEITEC MU supported by the National Center for Medical Genomics (NCMG) research infrastructure (LM22018132 funded by MEYS CR) and Core Facility Bioinformatics of CEITEC MU for their support in processing the data. This work was supported by the MEYS CR (Large RI Project LM2018129 Czech-BioImaging).
Publisher Copyright:
© 2021 American Society of Hematology
PY - 2021/9/2
Y1 - 2021/9/2
N2 - 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 CXCR4dimCD5bright vs CXCR4brightCD5dim 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 CXCR4brightCD5dim 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 (PI3K) activity and the “tonic” 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.
AB - 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 CXCR4dimCD5bright vs CXCR4brightCD5dim 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 CXCR4brightCD5dim 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 (PI3K) activity and the “tonic” 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.
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U2 - 10.1182/blood.2020008101
DO - 10.1182/blood.2020008101
M3 - Article
C2 - 33786575
AN - SCOPUS:85113306446
SN - 0006-4971
VL - 138
SP - 758
EP - 772
JO - Blood
JF - Blood
IS - 9
ER -