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-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.
Division of Transfusion Medicine and Cell Therapy, National Center for Geriatrics and Gerontology, 35 Gengo, Morioka-cho, Obu 474-8511, Japan. katsumi@ncgg.go.jp
Akira
A
Katsumi
Hitoshi
H
Kiyoi
Akihiro
A
Abe
Ryohei
R
Tanizaki
Toshihiro
T
Iwasaki
Miki
M
Kobayashi
Tadashi
T
Matsushita
Kozo
K
Kaibuchi
Takeshi
T
Senga
Tetsuhito
T
Kojima
Takayuki
T
Kohno
Michinari
M
Hamaguchi
Tomoki
T
Naoe
D000818:Animals; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D051418:Focal Adhesion Kinase 2 / Q000502:physiology*; D020440:Gene Duplication; D006801:Humans; D039041:Integrin alpha4beta1 / Q000502:physiology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D046912:Multiprotein Complexes; D009154:Mutation; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D000089804:Shelterin Complex; D015398:Signal Transduction; D020080:Tandem Repeat Sequences; D034501:Telomere-Binding Proteins / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology*
C523780:FI-700; D039041:Integrin alpha4beta1; D046912:Multiprotein Complexes; D011725:Pyridines; D011743:Pyrimidines; D000089804:Shelterin Complex; C440809:TERF2IP protein, human; D034501:Telomere-Binding Proteins; D019010:Vascular Cell Adhesion Molecule-1; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D051418:Focal Adhesion Kinase 2