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

Autor:	Seda V; Molecular Medicine, CEITEC Masaryk University, and.; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic., Vojackova E; Molecular Medicine, CEITEC Masaryk University, and., Ondrisova L; Molecular Medicine, CEITEC Masaryk University, and.; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic., Kostalova L; Molecular Medicine, CEITEC Masaryk University, and.; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic., Sharma S; Molecular Medicine, CEITEC Masaryk University, and., Loja T; Molecular Medicine, CEITEC Masaryk University, and., Mladonicka Pavlasova G; Molecular Medicine, CEITEC Masaryk University, and.; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic., Zicha D; Experimental Biophotonics, CEITEC University of Technology, Brno, Czech Republic., Kudlickova Peskova M; Centre for Neuroscience, CEITEC Masaryk University, Brno, Czech Republic., Krivanek J; Department of Histology and Embryology, Faculty of Medicine, and., Liskova K; Department of Pathology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic., Kren L; Department of Pathology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic., Benes V; Genomics Core Facility, EMBL (European Molecular Biology Laboratory), Heidelberg, Germany; and., Musilova Litzmanova K; Molecular Medicine, CEITEC Masaryk University, and.; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic., Borsky M; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic., Oppelt J; Molecular Medicine, CEITEC Masaryk University, and., Verner J; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic., Pospisilova S; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic., Brychtova Y; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic., Panovska A; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic., Tan Z; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX., Zhang S; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX., Doubek M; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic., Amruz Cerna K; Molecular Medicine, CEITEC Masaryk University, and.; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic., Mayer J; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic., Mraz M; Molecular Medicine, CEITEC Masaryk University, and.; Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2021 Sep 02; Vol. 138 (9), pp. 758-772.
DOI:	10.1182/blood.2020008101
Abstrakt:	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. (© 2021 by The American Society of Hematology.)
Databáze:	MEDLINE
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