Fms-like tyrosine kinase 3 ligand stimulation induces MLL-rearranged leukemia cells into quiescence resistant to antileukemic agents.
Fms-like tyrosine kinase 3 (FLT3) is highly expressed in acute lymphoblastic leukemia with the mixed-lineage leukemia (MLL) gene rearrangement refractory to chemotherapy. We examined the biological effect of FLT3-ligand (FL) on 18 B-precursor leukemic cell lines with variable karyotypic abnormalities, and found that nine of nine MLL-rearranged cell lines with wild-type FLT3, in contrast to other leukemic cell lines, are significantly inhibited in their proliferation in a dose-dependent manner by FL. This inhibition was due to induction of the G0-G1 arrest. A marked up-regulation of p27 by suppression of its protein degradation and an abrogation of constitutive signal transducers and activators of transcription 5 phosphorylation were revealed in arrested leukemia cells after FL stimulation. Importantly, FL treatment rendered not only cell lines but also primary leukemia cells with MLL rearrangement resistant to chemotherapeutic agents. MLL-rearranged leukemia cells adhering to the bone marrow stromal cell line, which expresses FL as the membrane-bound form, were induced to quiescent state resistant to chemotherapeutic agents, but their chemosensitivity was significantly restored in the presence of neutralizing anti-FL antibody. The FL/FLT3 interaction between leukemia cells and bone marrow stromal cells expressing FL at high levels should contribute, at least in part, to persistent minimal-residual disease of MLL-rearranged leukemia in bone marrow.
Furuichi
Yoshiyuki
Y
Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan.
Goi
Kumiko
K
Inukai
Takeshi
T
Sato
Hiroki
H
Nemoto
Atsushi
A
Takahashi
Kazuya
K
Akahane
Koshi
K
Hirose
Kinuko
K
Honna
Hiroko
H
Kuroda
Itaru
I
Zhang
Xiaochun
X
Kagami
Keiko
K
Hayashi
Yasuhide
Y
Harigaya
Kenichi
K
Nakazawa
Shinpei
S
Sugita
Kanji
K
D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002675:Child, Preschool; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004305:Dose-Response Relationship, Drug; D005260:Female; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D010766:Phosphorylation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D017154:Stromal Cells / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism
C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; C497422:KMT2A protein, human; D008565:Membrane Proteins; D050799:STAT5 Transcription Factor; C084881:flt3 ligand protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D051941:fms-Like Tyrosine Kinase 3; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases