Detail
Článek
Článek online
FT
Medvik - BMČ
  • Je něco špatně v tomto záznamu ?

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

V. Seda, E. Vojackova, L. Ondrisova, L. Kostalova, S. Sharma, T. Loja, G. Mladonicka Pavlasova, D. Zicha, M. Kudlickova Peskova, J. Krivanek, K. Liskova, L. Kren, V. Benes, K. Musilova Litzmanova, M. Borsky, J. Oppelt, J. Verner, S. Pospisilova,...

. 2021 ; 138 (9) : 758-772. [pub] 20210902

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc22003773

Grantová podpora
802644 European Research Council - International

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.

Citace poskytuje Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc22003773
003      
CZ-PrNML
005      
20220518110958.0
007      
ta
008      
220113s2021 xxu f 000 0|eng||
009      
AR
024    7_
$a 10.1182/blood.2020008101 $2 doi
035    __
$a (PubMed)33786575
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxu
100    1_
$a Seda, Vaclav $u Molecular Medicine, CEITEC Masaryk University, and $u Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
245    10
$a FoxO1-GAB1 axis regulates homing capacity and tonic AKT activity in chronic lymphocytic leukemia / $c V. Seda, E. Vojackova, L. Ondrisova, L. Kostalova, S. Sharma, T. Loja, G. Mladonicka Pavlasova, D. Zicha, M. Kudlickova Peskova, J. Krivanek, K. Liskova, L. Kren, V. Benes, K. Musilova Litzmanova, M. Borsky, J. Oppelt, J. Verner, S. Pospisilova, Y. Brychtova, A. Panovska, Z. Tan, S. Zhang, M. Doubek, K. Amruz Cerna, J. Mayer, M. Mraz
520    9_
$a 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.
650    _2
$a adaptorové proteiny signální transdukční $x biosyntéza $7 D048868
650    _2
$a adenin $x analogy a deriváty $x farmakologie $7 D000225
650    _2
$a nádorové buněčné linie $7 D045744
650    12
$a pohyb buněk $7 D002465
650    _2
$a forkhead box protein O1 $x metabolismus $7 D000071161
650    12
$a regulace genové exprese u leukemie $7 D015973
650    _2
$a lidé $7 D006801
650    _2
$a chronická lymfatická leukemie $x farmakoterapie $x metabolismus $x patologie $7 D015451
650    _2
$a piperidiny $x farmakologie $7 D010880
650    _2
$a protoonkogenní proteiny c-akt $x metabolismus $7 D051057
650    12
$a signální transdukce $7 D015398
650    12
$a upregulace $7 D015854
655    _2
$a časopisecké články $7 D016428
655    _2
$a práce podpořená grantem $7 D013485
700    1_
$a Vojackova, Eva $u Molecular Medicine, CEITEC Masaryk University, and
700    1_
$a Ondrisova, Laura $u Molecular Medicine, CEITEC Masaryk University, and $u Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
700    1_
$a Kostalova, Lenka $u Molecular Medicine, CEITEC Masaryk University, and $u Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
700    1_
$a Sharma, Sonali $u Molecular Medicine, CEITEC Masaryk University, and
700    1_
$a Loja, Tomas $u Molecular Medicine, CEITEC Masaryk University, and
700    1_
$a Mladonicka Pavlasova, Gabriela $u Molecular Medicine, CEITEC Masaryk University, and $u Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
700    1_
$a Zicha, Daniel $u Experimental Biophotonics, CEITEC University of Technology, Brno, Czech Republic $7 xx0272984
700    1_
$a Kudlickova Peskova, Marie $u Centre for Neuroscience, CEITEC Masaryk University, Brno, Czech Republic
700    1_
$a Krivanek, Jan $u Department of Histology and Embryology, Faculty of Medicine, and
700    1_
$a Liskova, Kvetoslava $u Department of Pathology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
700    1_
$a Kren, Leos $u Department of Pathology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
700    1_
$a Benes, Vladimir $u Genomics Core Facility, EMBL (European Molecular Biology Laboratory), Heidelberg, Germany; and
700    1_
$a Musilova Litzmanova, Katerina $u Molecular Medicine, CEITEC Masaryk University, and $u Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
700    1_
$a Borsky, Marek $u Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
700    1_
$a Oppelt, Jan $u Molecular Medicine, CEITEC Masaryk University, and
700    1_
$a Verner, Jan $u Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
700    1_
$a Pospisilova, Sarka $u Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
700    1_
$a Brychtova, Yvona $u Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
700    1_
$a Panovska, Anna $u Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
700    1_
$a Tan, Zhi $u Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
700    1_
$a Zhang, Shuxing $u Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
700    1_
$a Doubek, Michael $u Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
700    1_
$a Amruz Cerna, Katerina $u Molecular Medicine, CEITEC Masaryk University, and $u Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
700    1_
$a Mayer, Jiri $u Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
700    1_
$a Mraz, Marek $u Molecular Medicine, CEITEC Masaryk University, and $u Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
773    0_
$w MED00000807 $t Blood $x 1528-0020 $g Roč. 138, č. 9 (2021), s. 758-772
856    41
$u https://pubmed.ncbi.nlm.nih.gov/33786575 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y p $z 0
990    __
$a 20220113 $b ABA008
991    __
$a 20220518110954 $b ABA008
999    __
$a ok $b bmc $g 1751280 $s 1154922
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2021 $b 138 $c 9 $d 758-772 $e 20210902 $i 1528-0020 $m Blood $n Blood $x MED00000807
GRA    __
$a 802644 $p European Research Council $2 International
LZP    __
$a Pubmed-20220113

Najít záznam

Citační ukazatele

Možnosti archivace