FLT3/ ITD regulates leukaemia cell adhesion through α4β1 integrin and Pyk2 signalling

Internal tandem duplication of FMS‐like receptor tyrosine kinase 3 (FLT3/ITD) within its juxtamembrane domain is a frequent mutation in adult acute myeloid leukaemia (AML). This mutation causes constitutive activation of FLT3 and is associated with poor prognosis. The high relapse rate of FLT3/ITD‐p...

Full description

Saved in:
Bibliographic Details
Published in:European journal of haematology 2011-03, Vol.86 (3), p.191-198
Main Authors: Katsumi, Akira, Kiyoi, Hitoshi, Abe, Akihiro, Tanizaki, Ryohei, Iwasaki, Toshihiro, Kobayashi, Miki, Matsushita, Tadashi, Kaibuchi, Kozo, Senga, Takeshi, Kojima, Tetsuhito, Kohno, Takayuki, Hamaguchi, Michinari, Naoe, Tomoki
Format: Article
Language:English
Subjects:
Animals
Cell Adhesion - genetics
Cell Adhesion - physiology
Cell Line, Tumor
Coculture Techniques
FLT3
fms-Like Tyrosine Kinase 3 - antagonists & inhibitors
fms-Like Tyrosine Kinase 3 - genetics
fms-Like Tyrosine Kinase 3 - physiology
Focal Adhesion Kinase 2 - physiology
Gene Duplication
Humans
Integrin alpha4beta1 - physiology
leukaemia
Leukemia, Myeloid, Acute - drug therapy
Leukemia, Myeloid, Acute - genetics
Leukemia, Myeloid, Acute - pathology
Leukemia, Myeloid, Acute - physiopathology
Mice
Multiprotein Complexes
Mutation
Phosphorylation
Pyk2
Pyridines - pharmacology
Pyrimidines - pharmacology
Signal Transduction
Tandem Repeat Sequences
Telomere-Binding Proteins - metabolism
Vascular Cell Adhesion Molecule-1 - metabolism
α4β1 integrin
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Internal tandem duplication of FMS‐like receptor tyrosine kinase 3 (FLT3/ITD) within its juxtamembrane domain is a frequent mutation in adult acute myeloid leukaemia (AML). This mutation causes constitutive activation of FLT3 and is associated with poor prognosis. The high relapse rate of FLT3/ITD‐positive AML might be partly because of insufficient eradication of slow‐cycling leukaemic stem cells in the bone marrow microenvironment. β1 integrin mediates haematopoietic stem and progenitor cell homing along with their retention in the bone marrow and also inhibits haematopoietic proliferation and differentiation. Here, we demonstrate that inhibition of FLT3/ITD kinase activity by a FLT3 selective inhibitor named FI‐700 decreases affinity of α4β1 integrin to soluble VCAM‐1. α4β1 integrin deactivation by FI‐700 is independent of Rap1, which is the critical regulator of integrin inside‐out signalling. In addition, selective inhibition of FLT3/ITD induces Pyk2 dephosphorylation together with the inhibition of phosphatidylinositol‐3‐kinase (PI3K)/Akt pathway. Both wild‐type and ITD‐FLT3 proteins co‐immunoprecipitated with β1 integrin and Pyk2 indicating the signal crosstalk between FLT3, β1 integrin and Pyk2. These results collectively indicated that the inhibition of FLT3 kinase might contribute not only to the induction of apoptosis, but also to the leukaemia cell detachment from the bone marrow microenvironment in the treatment of AML.
ISSN:0902-4441
1600-0609
DOI:10.1111/j.1600-0609.2010.01556.x