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FLT3/ ITD regulates leukaemia cell adhesion through α4β1 integrin and Pyk2 signalling
Author(s) -
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
Publication year - 2011
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/j.1600-0609.2010.01556.x
Subject(s) - integrin , cancer research , microbiology and biotechnology , homing (biology) , integrin linked kinase , haematopoiesis , biology , bone marrow , protein kinase b , proto oncogene tyrosine protein kinase src , stem cell , chemistry , signal transduction , immunology , kinase , receptor , protein kinase a , cyclin dependent kinase 2 , ecology , biochemistry
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.