Proliferation and bone marrow engraftment of AML blasts is dependent on β-catenin signalling.
B-catenin is the central effector molecule of the canonical Wnt signalling pathway, which controls self-renewal of haematopoietic stem cells. Deregulation of this pathway occurs in various malignancies including myeloid leukaemias. The present study examined the functional outcome of stable β-catenin down-regulation through lentivirus-mediated expression of short hairpin RNA (shRNA). Reduction of the β-catenin levels in acute myeloid leukaemia (AML) cell lines and patient samples decelerated their in vitro proliferation ability without affecting cell viability. Transplantation of leukaemic cells with control or reduced levels of β-catenin in non-obese diabetic severe combined immunodeficient animals indicated that, while the immediate homing of the cells was unaffected, the bone marrow engraftment was directly dependent on β-catenin levels. Subsequent examination of bone sections revealed that β-catenin was implicated in the localization of AML to the endosteum. Examination of adhesion molecule expression before and after transplantation, revealed down-regulation of CD44 expression, accompanied by reduced in vitro adhesion. Gene expression analysis disclosed the presence of an autocrine compensatory mechanism, which responds to the reduced β-catenin levels by altering the expression of positive and negative pathway regulators. In conclusion, our study showed that β-catenin comprises an integral part of AML cell proliferation, cell cycle progression, and adhesion, and influences disease establishment in vivo.
Biomedical Research Foundation of the Academy of Athens, Greece. esiapati@bioacademy.gr
Elena K
EK
Siapati
Magda
M
Papadaki
Zoi
Z
Kozaou
Erasmia
E
Rouka
Evridiki
E
Michali
Ioanna
I
Savvidou
Dimitrios
D
Gogos
Despina
D
Kyriakou
Nikos I
NI
Anagnostopoulos
George
G
Vassilopoulos
D000328:Adult; D000368:Aged; D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D049109:Cell Proliferation; D018450:Disease Progression; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006085:Graft Survival / Q000502:physiology; D006801:Humans; D018960:Hyaluronan Receptors / Q000502:physiology; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology*; D009368:Neoplasm Transplantation; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D051176:beta Catenin / Q000378:metabolism / Q000502:physiology*
C497483:CD44 protein, human; D015815:Cell Adhesion Molecules; D018960:Hyaluronan Receptors; D009363:Neoplasm Proteins; D051176:beta Catenin