Publication detail

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

ŠEDA, V. VOJÁČKOVÁ, E. ONDRIŠOVÁ, L. KOŠŤÁLOVÁ, L. SHARMA, S. LOJA, T. MLADONICKÁ PAVLASOVÁ, G. ZICHA, D. PEŠKOVÁ, M. KŘIVÁNEK, J. LIŠKOVÁ, K. KŘEN, L. BENEŠ, V. MUSILOVÁ LITZMANOVÁ, K. BORSKÝ, M. OPPELT, J. VERNER, J. POSPÍŠILOVÁ, Š. BRYCHTOVÁ, Y. PANOVSKÁ, A. TAN, Z. ČERNÁ, K. MAYER, J. ZHANG, SX. DOUBEK, M. MRÁZ, M.

Original Title

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

Type

journal article in Web of Science

Language

English

Original Abstract

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.

Keywords

DOCKING PROTEIN GAB1; B-CELLS; BONE-MARROW; CHEMOKINE RECEPTOR; L-SELECTIN; P110-GAMMA ISOFORM; EPIDERMAL-GROWTH; TYROSINE KINASE; PI3 KINASE; IBRUTINIB

Authors

ŠEDA, V.; VOJÁČKOVÁ, E.; ONDRIŠOVÁ, L.; KOŠŤÁLOVÁ, L.; SHARMA, S.; LOJA, T.; MLADONICKÁ PAVLASOVÁ, G.; ZICHA, D.; PEŠKOVÁ, M.; KŘIVÁNEK, J.; LIŠKOVÁ, K.; KŘEN, L.; BENEŠ, V.; MUSILOVÁ LITZMANOVÁ, K.; BORSKÝ, M.; OPPELT, J.; VERNER, J.; POSPÍŠILOVÁ, Š.; BRYCHTOVÁ, Y.; PANOVSKÁ, A.; TAN, Z.; ČERNÁ, K.; MAYER, J.; ZHANG, SX.; DOUBEK, M.; ; MRÁZ, M.

Released

2. 9. 2021

Publisher

AMER SOC HEMATOLOGY

Location

WASHINGTON

ISBN

1528-0020

Periodical

Blood

Year of study

138

Number

9

State

United States of America

Pages from

758

Pages to

772

Pages count

15

URL

https://pubmed.ncbi.nlm.nih.gov/33786575/

BibTex

@article{BUT172865,
  author="ŠEDA, V. and VOJÁČKOVÁ, E. and ONDRIŠOVÁ, L. and KOŠŤÁLOVÁ, L. and SHARMA, S. and LOJA, T. and MLADONICKÁ PAVLASOVÁ, G. and ZICHA, D. and PEŠKOVÁ, M. and KŘIVÁNEK, J. and LIŠKOVÁ, K. and KŘEN, L. and BENEŠ, V. and MUSILOVÁ LITZMANOVÁ, K. and BORSKÝ, M. and OPPELT, J. and VERNER, J. and POSPÍŠILOVÁ, Š. and BRYCHTOVÁ, Y. and PANOVSKÁ, A. and TAN, Z. and ČERNÁ, K. and MAYER, J. and ZHANG, SX. and DOUBEK, M. and MRÁZ, M.",
  title="FoxO1-GAB1 axis regulates homing capacity and tonic AKT activity in chronic lymphocytic leukemia",
  journal="Blood",
  year="2021",
  volume="138",
  number="9",
  pages="758--772",
  doi="10.1182/blood.2020008101",
  issn="1528-0020",
  url="https://pubmed.ncbi.nlm.nih.gov/33786575/"
}