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

J 2021

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

ŠEDA, Václav; Eva VOJÁČKOVÁ; Laura ONDRIŠOVÁ; Lenka KOŠŤÁLOVÁ; Sonali SHARMA et. al.

Basic information

Original name

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

Authors

ŠEDA, Václav (203 Czech Republic, belonging to the institution); Eva VOJÁČKOVÁ (203 Czech Republic, belonging to the institution); Laura ONDRIŠOVÁ (703 Slovakia, belonging to the institution); Lenka KOŠŤÁLOVÁ (203 Czech Republic, belonging to the institution); Sonali SHARMA (356 India, belonging to the institution); Tomáš LOJA (703 Slovakia, belonging to the institution); Gabriela MLADONICKÁ PAVLASOVÁ (203 Czech Republic, belonging to the institution); Daniel ZICHA (203 Czech Republic); Marie KUDLIČKOVÁ PEŠKOVÁ (203 Czech Republic, belonging to the institution); Jan KŘIVÁNEK (203 Czech Republic, belonging to the institution); Květoslava MATULOVÁ (203 Czech Republic, belonging to the institution); Leoš KŘEN (203 Czech Republic, belonging to the institution); V. BENES; Markéta LITZMANOVÁ; Marek BORSKÝ (203 Czech Republic, belonging to the institution); Jan OPPELT (203 Czech Republic, belonging to the institution); Jan VERNER (203 Czech Republic, belonging to the institution); Šárka POSPÍŠILOVÁ (203 Czech Republic, belonging to the institution); Yvona BRYCHTOVÁ (203 Czech Republic, belonging to the institution); Anna PANOVSKÁ (203 Czech Republic, belonging to the institution); Z. TAN; S.X. ZHANG; Michael DOUBEK (203 Czech Republic, belonging to the institution); Kateřina AMRUZ ČERNÁ (203 Czech Republic, belonging to the institution); Jiří MAYER (203 Czech Republic, belonging to the institution) and Marek MRÁZ (203 Czech Republic, guarantor, belonging to the institution)

Edition

Blood, Washington DC, USA, American Society of Hematology, 2021, 0006-4971

Other information

Language

English

Type of outcome

Article in a journal

Field of Study

30205 Hematology

Country of publisher

United States of America

Confidentiality degree

is not subject to a state or trade secret

References:

URL

Impact factor

Impact factor: 25.669

RIV identification code

RIV/00216224:14740/21:00123376

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.1182/blood.2020008101

UT WoS

000692441100006

EID Scopus

2-s2.0-85113306446

Keywords in English

DOCKING PROTEIN GAB1B-CELLSBONE-MARROWCHEMOKINE RECEPTORL-SELECTINP110-GAMMA ISOFORMEPIDERMAL-GROWTHTYROSINE KINASEPI3 KINASEIBRUTINIB

Abstract

In the original language

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 "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.

Links

LM2018129, research and development project

Name: Národní infrastruktura pro biologické a medicínské zobrazování Czech-BioImaging

Investor: Ministry of Education, Youth and Sports of the CR

MUNI/A/1595/2020, interní kód MU

Name: Nové přístupy ve výzkumu, diagnostice a terapii hematologických malignit VIII (Acronym: VýDiTeHeMa VIII)

Investor: Masaryk University

802644, interní kód MU

Name: Signaling propensity in the microenvironment of B cell chronic lymphocytic leukemia (Acronym: LeukemiaEnviron)

Investor: European Union, ERC (Excellent Science)

90132, large research infrastructures

Name: NCMG II

Files attached

FoxO1-GAB1_axis_regulates_homing_capacity_and_tonic.pdf

Cite

ŠEDA, Václav; Eva VOJÁČKOVÁ; Laura ONDRIŠOVÁ; Lenka KOŠŤÁLOVÁ; Sonali SHARMA; Tomáš LOJA; Gabriela MLADONICKÁ PAVLASOVÁ; Daniel ZICHA; Marie KUDLIČKOVÁ PEŠKOVÁ; Jan KŘIVÁNEK; Květoslava MATULOVÁ; Leoš KŘEN; V. BENES; Markéta LITZMANOVÁ; Marek BORSKÝ; Jan OPPELT; Jan VERNER; Šárka POSPÍŠILOVÁ; Yvona BRYCHTOVÁ; Anna PANOVSKÁ; Z. TAN; S.X. ZHANG; Michael DOUBEK; Kateřina AMRUZ ČERNÁ; Jiří MAYER and Marek MRÁZ. FoxO1-GAB1 axis regulates homing capacity and tonic AKT activity in chronic lymphocytic leukemia. Blood. Washington DC, USA: American Society of Hematology, 2021, vol. 138, No 9, p. 758-772. ISSN 0006-4971. Available from: https://dx.doi.org/10.1182/blood.2020008101.

@article{1813384,
   author = {Šeda, Václav and Vojáčková, Eva and Ondrišová, Laura and Košťálová, Lenka and Sharma, Sonali and Loja, Tomáš and Mladonická Pavlasová, Gabriela and Zicha, Daniel and Kudličková Pešková, Marie and Křivánek, Jan and Matulová, Květoslava and Křen, Leoš and Benes, V. and Litzmanová, Markéta and Borský, Marek and Oppelt, Jan and Verner, Jan and Pospíšilová, Šárka and Brychtová, Yvona and Panovská, Anna and Tan, Z. and Zhang, S.X. and Doubek, Michael and Amruz Černá, Kateřina and Mayer, Jiří and Mráz, Marek},
   article_location = {Washington DC, USA},
   article_number = {9},
   doi = {http://dx.doi.org/10.1182/blood.2020008101},
   keywords = {DOCKING PROTEIN GAB1B-CELLSBONE-MARROWCHEMOKINE RECEPTORL-SELECTINP110-GAMMA ISOFORMEPIDERMAL-GROWTHTYROSINE KINASEPI3 KINASEIBRUTINIB},
   language = {eng},
   issn = {0006-4971},
   journal = {Blood},
   title = {FoxO1-GAB1 axis regulates homing capacity and tonic AKT activity in chronic lymphocytic leukemia},
   url = {https://ashpublications.org/blood/article/138/9/758/475649/FoxO1-GAB1-axis-regulates-homing-capacity-and},
   volume = {138},
   year = {2021}
}

TY  - JOUR
ID  - 1813384
AU  - Šeda, Václav - Vojáčková, Eva - Ondrišová, Laura - Košťálová, Lenka - Sharma, Sonali - Loja, Tomáš - Mladonická Pavlasová, Gabriela - Zicha, Daniel - Kudličková Pešková, Marie - Křivánek, Jan - Matulová, Květoslava - Křen, Leoš - Benes, V. - Litzmanová, Markéta - Borský, Marek - Oppelt, Jan - Verner, Jan - Pospíšilová, Šárka - Brychtová, Yvona - Panovská, Anna - Tan, Z. - Zhang, S.X. - Doubek, Michael - Amruz Černá, Kateřina - Mayer, Jiří - Mráz, Marek
PY  - 2021
TI  - FoxO1-GAB1 axis regulates homing capacity and tonic AKT activity in chronic lymphocytic leukemia
JF  - Blood
VL  - 138
IS  - 9
SP  - 758-772
EP  - 758-772
PB  - American Society of Hematology
SN  - 00064971
KW  - DOCKING PROTEIN GAB1B-CELLSBONE-MARROWCHEMOKINE RECEPTORL-SELECTINP110-GAMMA ISOFORMEPIDERMAL-GROWTHTYROSINE KINASEPI3 KINASEIBRUTINIB
UR  - https://ashpublications.org/blood/article/138/9/758/475649/FoxO1-GAB1-axis-regulates-homing-capacity-and
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 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 "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.
ER  -

ŠEDA, Václav; Eva VOJÁČKOVÁ; Laura ONDRIŠOVÁ; Lenka KOŠŤÁLOVÁ; Sonali SHARMA; Tomáš LOJA; Gabriela MLADONICKÁ PAVLASOVÁ; Daniel ZICHA; Marie KUDLIČKOVÁ PEŠKOVÁ; Jan KŘIVÁNEK; Květoslava MATULOVÁ; Leoš KŘEN; V. BENES; Markéta LITZMANOVÁ; Marek BORSKÝ; Jan OPPELT; Jan VERNER; Šárka POSPÍŠILOVÁ; Yvona BRYCHTOVÁ; Anna PANOVSKÁ; Z. TAN; S.X. ZHANG; Michael DOUBEK; Kateřina AMRUZ ČERNÁ; Jiří MAYER and Marek MRÁZ. FoxO1-GAB1 axis regulates homing capacity and tonic AKT activity in chronic lymphocytic leukemia. \textit{Blood}. Washington DC, USA: American Society of Hematology, 2021, vol.~138, No~9, p.~758-772. ISSN~0006-4971. Available from: https://dx.doi.org/10.1182/blood.2020008101.

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